FormalPara Key Summary Points

Why carry out this study?

Individuals with chronic hypoparathyroidism who are managed with conventional therapy (active vitamin D and calcium) are at increased risk for deleterious renal complications (e.g., nephrocalcinosis and nephrolithiasis) and have a higher incidence of chronic kidney disease compared with age-matched healthy individuals.

This post hoc analysis of the pivotal phase 3 PaTHway trial examined the impact of palopegteriparatide treatment on parameters of renal function in adults with chronic hypoparathyroidism, including a subanalysis of those with a baseline estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2.

What was learned from the study?

Treatment with palopegteriparatide over 52 weeks in the PaTHway trial resulted in a mean increase in eGFR of 9.3 mL/min/1.73 m2 from baseline (P < 0.0001), with 43% of participants experiencing an increase from baseline in eGFR ≥ 10 mL/min/1.73 m2.

Numerically higher increases in mean eGFR were observed for participants with baseline eGFR < 60 mL/min/1.73 m2, indicating that palopegteriparatide treatment may be particularly beneficial to adults with chronic hypoparathyroidism who have a reduction in renal function.

The results of this post hoc analysis suggest that transitioning from conventional therapy to PTH replacement therapy with palopegteriparatide may preserve or improve renal function as observed in adults with chronic hypoparathyroidism over 1 year in the PaTHway trial.

Introduction

Hypoparathyroidism is an endocrine disease caused by insufficient levels of parathyroid hormone (PTH) and is associated with substantial morbidity, poor quality of life, and increased healthcare utilization [1, 2]. According to a recent systematic literature review, chronic hypoparathyroidism is associated with an increased prevalence of renal complications, such as nephrolithiasis (up to 36%), nephrocalcinosis (up to 38%), and chronic kidney disease (CKD) (up to 41%) [3]. Compared to individuals without chronic hypoparathyroidism, those with chronic hypoparathyroidism are also at increased risk for substantial declines in renal function, CKD stage progression, and development of end-stage renal disease [4].

While the exact mechanisms responsible for this increased risk of renal complications in chronic hypoparathyroidism are not fully understood, they are hypothesized to develop in part as a result of the chronically elevated serum phosphate levels, high calcium × phosphate product, serum calcium fluctuations, and hypercalciuria which are characteristic of chronic hypoparathyroidism managed with conventional therapy with long-term use of active vitamin D and elemental calcium [1, 3, 5]. Therefore, treatments that replace the physiologic effects of PTH and minimize or remove the need for conventional therapy may provide beneficial effects on renal outcomes in the setting of chronic hypoparathyroidism. Palopegteriparatide (TransCon PTH, approved under the brand name YORVIPATH® in the European Union and certain other countries as a replacement therapy indicated for the treatment of adults with chronic hypoparathyroidism) is a prodrug of PTH (1–34), administered as a once-daily subcutaneous injection, with sustained release of active PTH designed to provide PTH levels in the physiological range for 24 h/day [6]. In the 26-week randomized, double-blind, placebo-controlled period of the pivotal phase 3 PaTHway trial, significantly more participants treated with palopegteriparatide (n = 48/61, 79%) than placebo (n = 1/21, 5%) met the primary multicomponent efficacy endpoint, defined as normocalcemia and independence from conventional therapy (a standing dose of active vitamin D equal to zero and ≤ 600 mg elemental calcium) without an increase in prescribed study drug over the 4 weeks prior to week 26 (P < 0.0001) [7]. To better understand the impact of palopegteriparatide on renal function in this vulnerable population, a post hoc analysis was performed to evaluate the longitudinal effect of palopegteriparatide on renal function in adults with chronic hypoparathyroidism through week 52 of the PaTHway trial.

Methods

Trial Design

PaTHway is a phase 3 trial, including a randomized, double-blind, placebo-controlled 26-week period followed by an ongoing 156-week open-label extension period designed to assess the efficacy, safety, and tolerability of palopegteriparatide in adults with chronic hypoparathyroidism. Details of the trial design were published previously [7]. Briefly, the trial enrolled adult men and non-pregnant women (≥ 18 years of age) with chronic hypoparathyroidism for a duration of at least 6 months, including individuals with postsurgical, autoimmune, genetic, and idiopathic etiologies. Trial inclusion criteria required participants to have an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 at screening. Thiazide diuretic use was not allowed within 4 weeks prior to the 24-h urine collection before visit 1 and the use of loop diuretics and phosphate binders (other than calcium supplements) was not permitted during the trial. Upon enrollment, participants were randomized 3:1 to subcutaneously administered palopegteriparatide (initially 18 μg PTH (1–34)/day) or a corresponding volume of placebo, both co-administered with conventional therapy (active vitamin D and calcium). Palopegteriparatide and placebo were titrated and conventional therapy was reduced/removed according to a protocol-specified dosing algorithm guided by serum calcium levels. At the week 26 visit, participants randomized to placebo during the blinded period initiated palopegteriparatide treatment (18 μg PTH (1–34)/day) in addition to conventional therapy and were individually and progressively titrated to an optimal dose concurrent with reduction/removal of conventional therapy using the same protocol-specified dosing algorithm. The protocol was reviewed by the appropriate institutional review boards and independent ethics committees (please see Supplementary Material Table S1 for a list of trial site ethics committees). The trial was designed by the sponsor and authors and conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines as described in the International Conference on Harmonization Guideline E6. All participants provided signed informed consent before treatment initiation. Results through week 52 of the PaTHway trial are reported herein.

Outcome Measures

Treatment Efficacy

Palopegteriparatide treatment efficacy in the open-label extension period of the PaTHway trial was assessed by a multicomponent endpoint defined as the proportion of participants with normocalcemia (defined as albumin-adjusted serum calcium 8.3–10.6 mg/dL [2.1–2.6 mmol/L]) and independence from conventional therapy. Independence from conventional therapy was defined as a standing dose of active vitamin D equal to zero and a standing dose of elemental calcium ≤ 600 mg on the day prior to the visit of interest.

Renal Function

Renal function was assessed by eGFR calculated according to the Modified Diet in Renal Disease (MDRD) equation as follows: eGFR (mL/min/1.73 m2) = 175 × (serum creatinine mg/dL)−1.154 × (age)−0.203 × 0.742 [if female] × 1.212 [if Black] [8]. In the PaTHway trial, eGFR was calculated at baseline and regular intervals throughout the blinded and open-label extension periods. Outcomes of interest included mean eGFR at prespecified time points throughout the trial and changes in eGFR from baseline through week 52. To further evaluate the impact of study treatment over time, a responder analysis was performed to determine the percentage of participants with a clinically meaningful change from baseline in eGFR (≥ 5 mL/min/1.73 m2) [9, 10] as well as a change from baseline ≥ 10 mL/min/1.73 m2 at weeks 26 and 52. All renal outcome measures were assessed for the total trial population by randomized treatment allocation (palopegteriparatide and placebo/palopegteriparatide) and stratified by baseline renal function (eGFR < 60 and ≥ 60 mL/min/1.73 m2).

Safety

Treatment safety assessments included 24-h urine biochemistries collected at prespecified time points throughout the blinded and open-label periods of the trial and treatment-emergent adverse events (TEAE). Trial investigators evaluated the seriousness, severity, and causality of all reported TEAEs. Adverse events were coded by system organ class (SOC) and preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) Version 24.0 or newer.

Statistical Analyses

Data are summarized descriptively by treatment group with continuous variables presented as mean and standard deviation (SD) and categorical data presented using counts (n) and percentages of participants. At post-baseline visits, only data from participants with both baseline and the corresponding visit values were used to compute statistical summaries. Paired t tests were used to determine if changes from baseline in eGFR in individual treatment groups were greater than zero. Changes in eGFR between treatment groups were analyzed using an analysis of covariance (ANCOVA) model with change from baseline in eGFR as the dependent variable; treatment, baseline eGFR group, and sex as fixed effects; and baseline eGFR and age as covariates. eGFR slope and 95% confidence intervals were estimated using a mixed model repeated measures (MMRM) model with change in eGFR as the dependent variable, baseline eGFR and visit in weeks as covariates, and participant as a random effect. This can be expressed as ([eGFR − baseline eGFR]/time in weeks) to estimate the change in eGFR per week, adjusting for baseline eGFR. Changes at week 0 were set as 0. Slopes were estimated separately for participants randomized to palopegteriparatide and placebo from baseline to week 4, weeks 4–12, 12–26, and 26–52. All statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

Participant Demographics and Baseline Characteristics

Of the 82 participants who were randomized to treatment and received at least one dose of blinded study drug in the PaTHway trial (n = 61 palopegteriparatide, n = 21 placebo), 79 completed blinded treatment through week 26, and 78 completed week 52 (n = 59 palopegteriparatide, n = 19 placebo/palopegteriparatide). Overall, participants were predominately female and white with a mean (SD) baseline age of 48.6 (12.7) years. The mean (SD) duration of hypoparathyroidism at baseline was 12 (11.4) years and 85% (n = 70/82) of participants had chronic hypoparathyroidism acquired from neck surgery (Table 1). Non-surgical etiologies of chronic hypoparathyroidism included primary idiopathic disease (n = 7), autoimmune polyglandular syndrome type 1 (APS-1) (n = 2), autosomal dominant hypocalcemia (activating mutation of the calcium-sensing receptor [CaSR]) (n = 1), HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal disease; also known as Barakat syndrome) (n = 1), and DiGeorge syndrome (n = 1). The treatment groups were balanced with respect to age, sex, race, and baseline hypoparathyroidism characteristics. The prevalence of hypertension and diabetes and the use of medications that may affect eGFR were comparable between randomization groups.

Table 1 Baseline demographics and clinical characteristics of PaTHway trial participants by baseline renal function
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Mean (SD) baseline eGFR was 67.3 (13.7) mL/min/1.73 m2 in participants randomized to palopegteriparatide and 72.7 (14.6) mL/min/1.73 m2 in those randomized to placebo. Among participants receiving renin-angiotensin system (RAS) blockers at baseline, mean (SD) eGFR was similar to the overall population (palopegteriparatide, 65.1 (18.9) mL/min/1.73 m2; placebo, 70.8 (20.5) mL/min/1.73 m2). At baseline, 28% (n = 23/82; n = 19 palopegteriparatide, n = 4 placebo) of participants had eGFR < 60 mL/min/1.73 m2 and 72% (n = 59/82, n = 42 palopegteriparatide, n = 17 placebo) had eGFR ≥ 60 mL/min/1.73 m2. Participants with eGFR < 60 mL/min/1.73 m2 were older, had higher mean baseline doses of active vitamin D and elemental calcium, longer duration of hypoparathyroidism, and more cases of non-surgical etiology of hypoparathyroidism than those with eGFR ≥ 60 mL/min/1.73 m2 (Table 1).

Efficacy

During the blinded period of the PaTHway trial, palopegteriparatide treatment enabled rapid and sustained reduction of elemental calcium doses and complete discontinuation of active vitamin D within 8 weeks [7]. Overall, 81% (n = 63/78) of participants treated with palopegteriparatide through week 52 of the open-label extension met the multicomponent efficacy endpoint and 95% (n = 74/78) achieved independence from conventional therapy (a standing dose of active vitamin D equal to zero and elemental calcium ≤ 600 mg on the day prior to the week 52 visit). All participants with baseline eGFR < 60 mL/min/1.73 m2 remained independent from conventional therapy at week 52; 79% in the palopegteriparatide group (n = 15/19) and 50% in the placebo/palopegteriparatide group (n = 2/4) also had albumin-adjusted serum calcium levels within the normal range (8.3–10.6 mg/dL [2.1–2.6 mmol/L]) at week 52 (Table 2). Among participants with baseline eGFR ≥ 60 mL/min/1.73 m2 and data on all efficacy components at week 52, 83% (n = 33/40) in the palopegteriparatide group and 87% (n = 13/15) in the placebo/palopegteriparatide group achieved independence from conventional therapy and maintained serum calcium within the normal range.

Table 2 Multicomponent efficacy outcome at week 52 of the PaTHway trial by baseline renal function
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Renal Function

During the 26-week blinded period, treatment with palopegteriparatide resulted in statistically significant improvements in eGFR compared with placebo for all participants and for both baseline eGFR subgroups < 60 and ≥ 60 mL/min/1.73 m2 (all P < 0.05) (Table 3). At week 26, mean (SD) eGFR rose by 7.9 (10.4) mL/min/1.73 m2 in the palopegteriparatide group and fell by 1.9 (8.6) mL/min/1.73 m2 in the placebo group (P < 0.001 for the difference between groups). At week 52, there was an additional eGFR rise in the palopegteriparatide group, and the mean (SD) eGFR was 9.3 (11.7) mL/min/1.73 m2 higher as compared with the baseline (P < 0.001). For participants randomized to placebo who received open-label palopegteriparatide starting at week 26, mean (SD) eGFR rose and was 7.6 (8.7) mL/min/1.73 m2 (P < 0.01) higher at week 52 compared to baseline (Table 3, Fig. 1). Trends in mean eGFR changes from baseline to weeks 26 and 52 in participants receiving RAS blockers at baseline were consistent with results for the overall population (Supplementary Material Table S2). At weeks 4 and 12, there was a weak negative correlation between the change from baseline in eGFR and the change from baseline in the dose of active vitamin D in both treatment groups (r = − 0.2 to − 0.4). No correlation was observed at week 26. For participants who switched from placebo to palopegteriparatide at week 26, there was a negative correlation between the change in eGFR and the change in active vitamin D dose from baseline to week 52 (r = − 0.5). At weeks 12, 26, and 52 weak negative correlations were also observed between the change from baseline in eGFR and the change from baseline in elemental calcium dose in participants randomized to palopegteriparatide (r = − 0.2 to − 0.3) but not in participants randomized to placebo.

Table 3 Change in eGFR from baseline at week 26 and week 52 in PaTHway trial participants
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Fig. 1
figure 1

Mean (SD) changes from baseline in eGFR through week 52 of the PaTHway trial for the overall population and by baseline eGFR subgroup (< 60 or ≥ 60 mL/min/1.73 m2). Participants randomized to palopegteriparatide at baseline (n = 61) are shown in dark blue, and participants randomized to placebo (n = 21) are shown in white during the blinded period and light blue starting at week 26 when palopegteriparatide treatment was initiated (shaded region). At baseline, 19 participants randomized to palopegteriparatide and 4 randomized to placebo had baseline eGFR < 60 mL/min/1.73 m2. Abbreviations: eGFR, estimated glomerular filtration rate; SD, standard deviation

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The mean change in eGFR from baseline through week 52 was numerically greater for participants with baseline eGFR < 60 mL/min/1.73 m2 (Table 3, Fig. 1). In participants randomized to palopegteriparatide with baseline eGFR < 60 mL/min/1.73 m2 (n = 19), the mean (SD) change in eGFR from baseline was 11.4 (10.7) mL/min/1.73 m2 at week 26 (P < 0.0001) and 11.5 (11.3) mL/min/1.73 m2 (P < 0.001) at week 52. Of these 19 participants, 10 had an eGFR ≥ 60 mL/min/1.73 m2 at week 52. Participants randomized to placebo with baseline eGFR < 60 mL/min/1.73 m2 (n = 4) had no change in mean (SD) eGFR (0.1 [6.0] mL/min/1.73 m2; P ≥ 0.05) at week 26 but following 26 weeks of palopegteriparatide treatment in the open-label extension the mean (SD) eGFR rose and was 11.7 (2.2) mL/min/1.73 m2 (P < 0.01) higher than baseline at week 52.

In the overall trial population and subgroup analysis by baseline eGFR, palopegteriparatide treatment demonstrated a rapid increase in eGFR evident as early as week 4 and sustained improvement through week 52. Across treatment groups, the slope (95% CI) of the change in eGFR from baseline to week 4 was similar (palopegteriparatide, 1.3 [0.6, 1.9] mL/min/1.73 m2/week [P < 0.0001]; placebo, 1.2 [0.3, 2.1] mL/min/1.73 m2/week [P < 0.01]). After week 4, participants randomized to palopegteriparatide had stabilization of eGFR, with slope (95% CI) of change in eGFR of 0.2 (− 0.2, 0.6) mL/min/1.73 m2/week from week 4 to 12 (P ≥ 0.05), 0.1 (− 0.1, 0.3) mL/min/1.73 m2/week from week 12 to 26 (P ≥ 0.05), and 0.1 (− 0.1, 0.2) mL/min/1.73 m2/week from week 26 to 52 (P ≥ 0.05). Conversely, participants randomized to placebo had a negative slope (95% CI) of change in eGFR of − 0.2 (− 0.8, 0.3) mL/min/1.73 m2/week from week 4 to 12 (P ≥ 0.05) and − 0.4 (− 0.8, − 0.1) mL/min/1.73 m2/week from week 12 to 26 (P < 0.05). After starting palopegteriparatide at week 26, the slope (95% CI) of change in eGFR significantly increased to 0.3 (0.1, 0.5) mL/min/1.73 m2/week from week 26 to 52 (P < 0.01).

At week 52, 64% (n = 39/61) of participants in the palopegteriparatide group had a ≥ 5 mL/min/1.73 m2 increase and 43% (n = 26/61) had a ≥ 10 mL/min/1.73 m2 increase in eGFR from baseline (Fig. 2). Of the participants with baseline eGFR < 60 mL/min/1.73 m2, 68% (n = 13/19) in the palopegteriparatide group and 100% (n = 4/4) in the placebo/palopegteriparatide group had a ≥ 5 mL/min/1.73 m2 increase in eGFR from baseline to week 52 and 42% (n = 8/19) in the palopegteriparatide and 75% (n = 3/4) in the placebo/palopegteriparatide group had a ≥ 10 mL/min/1.73 m2 increase. In summary, palopegteriparatide treatment resulted in a rapid and sustained increase in mean eGFR across all subgroups, with the greatest improvement seen in those with impaired renal function at baseline.

Fig. 2
figure 2

Proportion of participants from the PaTHway trial with an increase ≥ 5 mL/min/1.73 m2 and ≥ 10 mL/min/1.73 m2 in eGFR from baseline to weeks 26 and 52. Participants randomized to palopegteriparatide at baseline (n = 61) are shown in dark blue, and participants randomized to placebo (n = 21) are shown in white during the blinded period and light blue starting at week 26 when palopegteriparatide treatment was initiated. Abbreviations: eGFR, estimated glomerular filtration rate

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Safety

At week 52, mean serum and 24-h urine biochemistries were similar across baseline eGFR and treatment allocation subgroups (Table 4). In participants randomized to palopegteriparatide during the blinded period, mean (SD) 24-h urine calcium levels decreased from 392 (175) mg/24 h at baseline to 220 (123) mg/24 h at week 26 and remained below the upper limit of normal (≤ 250 mg/24 h) with a mean (SD) of 185 (121) mg/24 h at week 52. With the initiation of palopegteriparatide treatment at week 26, mean (SD) 24-h urine calcium levels in the placebo/palopegteriparatide group decreased from 292 (125) mg/24 h at week 26 to 223 (89) mg/24 h at week 52.

Table 4 Serum and urine biochemistries at week 52 by baseline renal function in PaTHway trial participants
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Overall, TEAEs were reported at similar rates between participants with baseline eGFR < 60 and ≥ 60 mL/min/1.73 m2. One case of nephrolithiasis was reported for a participant in the placebo group during blinded treatment; none were reported through week 52 with palopegteriparatide. A higher percentage of serious TEAEs unrelated to treatment (n = 4/23, 17% vs. n = 4/57, 7%) and TEAEs related to hyper- or hypocalcemia leading to emergency room/urgent care visits and/or hospitalization (n = 4/23, 17% vs. n = 2/57, 4%) were reported in participants with baseline eGFR < 60 mL/min/1.73 m2 than those with eGFR ≥ 60 mL/min/1.73 m2, respectively.

Discussion

Treatment with palopegteriparatide was associated with significant and sustained improvement in renal function, as measured by mean eGFR, in adults with chronic hypoparathyroidism in this post hoc analysis of the phase 3 PaTHway trial. Overall, 64% of participants treated with palopegteriparatide for 52 weeks had a clinically meaningful change in eGFR of ≥ 5 mL/min/1.73 m2. Mean eGFR rose by 9.3 mL/min/1.73 m2 and 43% of participants had a ≥ 10 mL/min/1.73 m2 increase in eGFR by week 52 of the PaTHway trial. This effect was greatest amongst the subgroup with baseline eGFR < 60 mL/min/1.73 m2 who received 52 weeks of treatment with palopegteriparatide, which had a mean increase in eGFR of 11.5 mL/min/1.73 m2 from baseline to week 52. In this subgroup, 68% of participants had a clinically meaningful change in eGFR and 42% had a ≥ 10 mL/min/1.73 m2 increase in eGFR by week 52. Treatment efficacy with palopegteriparatide was generally consistent across baseline eGFR levels.

The increased risk of renal complications among individuals with chronic hypoparathyroidism managed with conventional therapy compared with the general population has been well described [3]. A large retrospective cohort study from a US managed care claims database of 8097 individuals with chronic hypoparathyroidism treated with conventional therapy but not PTH therapy and 40,485 without chronic hypoparathyroidism found that those with chronic hypoparathyroidism had a significant two- to threefold increased risk of development and progression of CKD, eGFR decline, and progression to end-stage renal disease compared with those without hypoparathyroidism [4]. Results of a retrospective analysis of US Medicare claims data found a similarly significantly increased risk of renal events (moderate or severe renal disease, nephrolithiasis, or nephrocalcinosis) in adults with postsurgical chronic hypoparathyroidism compared with those without [11].

The mechanisms underlying the increased risk of renal complications in chronic hypoparathyroidism are not definitively established. They are hypothesized to develop in part as a result of the chronically elevated serum phosphate levels, high calcium × phosphate product, serum calcium fluctuations, and hypercalciuria which are characteristic of chronic hypoparathyroidism managed with conventional therapy with long-term use of active vitamin D and elemental calcium [1, 3, 5]. Though conventional therapy for hypoparathyroidism aims to alleviate hypocalcemia, it does not address the consequences of chronic PTH insufficiency [12] and carries its own iatrogenic risks—such as renal injury. According to the 2022 Guidelines from the Second International Workshop, PTH replacement therapy should be considered for individuals who are not adequately controlled on conventional therapy, including those with renal insufficiency or hypercalciuria [2].

Several retrospective cohort studies of adults with chronic hypoparathyroidism treated with PTH therapy as an adjunctive treatment to conventional therapy had preservation of eGFR over 5 years, in contrast to a decline in eGFR in historical control cohorts [13,14,15]. A retrospective cohort study by Rejnmark et al. showed that participants with chronic hypoparathyroidism from randomized, double-blind, placebo-controlled trials and open-label studies treated with recombinant human (rh) PTH (1–84) had a 53% lower risk of developing CKD (HR 0.5, 95% CI 0.3–0.9) and 65% lower risk for sustained eGFR decline ≥ 30% from baseline (HR 0.4, 95% CI 0.1–0.9) compared with a historical control cohort of adults with chronic hypoparathyroidism selected from an electronic medical record database who had a prescription for active vitamin D but no use of rhPTH (1–84) or teriparatide [15]. These findings suggest that, in contrast to conventional therapy, PTH therapy may have a protective effect on renal function in individuals with hypoparathyroidism.

In this post hoc analysis of the PaTHway trial, mean eGFR increased by 9.3 mL/min/1.73 m2 with palopegteriparatide treatment over 52 weeks and by 7.6 mL/min/1.73 m2 in participants randomized to placebo during the blinded treatment period who received open-label palopegteriparatide from weeks 26 to 52. The largest changes in eGFR in the palopegteriparatide group occurred during the first 4 weeks and were potentially due to a combination of PTH-driven tubular reabsorption of calcium and excretion of phosphate, the vasodilatory effects of PTH on the renal vasculature [16], and the net effect of PTH on glomerular hemodynamics [17, 18]. Additionally, a significant reduction in the dose of conventional therapy (including almost complete independence from active vitamin D and a 70% reduction in the dose of elemental calcium by week 4), and therefore, reduction in calcium influx and excretion could be contributing factors. Further studies are needed to investigate these potential causes of improved eGFR. A transient increase in eGFR during the first 4 weeks was also observed in the placebo group whose participants had a 50% reduction in active vitamin D dose but not in elemental calcium [7]. This less pronounced decrease in conventional therapy in the placebo group was maintained during the 26-week blinded period but associated with an overall net decline in eGFR from baseline to week 26. However, mean eGFR increased once palopegteriparatide was started in these participants, mirroring the increases observed in the palopegteriparatide group. Correlation analyses demonstrate weak correlations between decreases in active vitamin D from baseline to weeks 4 and 12 and increases in eGFR from baseline to these time points in both treatment groups. However, no correlation remained at week 26. A moderate inverse correlation between changes from baseline in active vitamin D doses and eGFR was observed in the placebo group at week 52. Decreases in elemental calcium doses were weakly correlated with increases in eGFR in participants randomized to palopegteriparatide and no correlations were observed at any time point for those randomized to placebo. As such, clinically meaningful reduction in conventional therapy in isolation is not sufficient to explain the observed improvement in renal function.

There is a fundamental difference between conventional therapy and PTH replacement with respect to the normalization of serum calcium. Conventional therapy increases serum calcium but does not replace the missing or insufficient PTH action on the kidneys and other target organs. Although it is not possible to fully determine what proportion of eGFR improvement was due to changes in conventional therapy alone versus the direct effects of palopegteriparatide itself, it is critical to note that independence from conventional therapy would not be possible without palopegteriparatide as was observed in the placebo arm. Therefore, it is plausible to conclude that palopegteriparatide has both direct and indirect effects underlying the observed improvement in eGFR. The findings of the present study are in contrast with the 24-week phase 3, randomized, double-blind, placebo-controlled REPLACE trial [19] and 5-year post hoc analysis of the RACE study [20], which showed preservation of renal function with rhPTH (1–84) but not a sustained increase in eGFR from baseline.

There are several key differences between rhPTH (1–84) and palopegteriparatide. First, rhPTH (1–84) has a half-life of approximately 3 h, and, consequently, once-daily administration results in wide fluctuations in PTH levels over the dosing period, with an initial supraphysiologic peak followed by a decline to pre-dose levels at approximately 12 h [21]. In contrast, palopegteriparatide was designed to provide continuous PTH exposure with a long half-life relative to the 24-h dosing interval resulting in a low peak-to-trough ratio. Palopegteriparatide has an apparent half-life of 60 h, with 24-h sustained release of active PTH within the physiological range [6]. In PaTHway, more than 90% of participants achieved independence from conventional therapy by week 26, increasing to 95% of participants by week 52 [7, 22]. By contrast, only approximately 40% of participants receiving rhPTH (1–84) achieved independence from conventional therapy through week 24 in REPLACE [19]. In participants randomized to palopegteriparatide in the PaTHway trial, active vitamin D and elemental calcium were nearly completely withdrawn by weeks 4 and 8, respectively [7]. While changes in urine calcium excretion were similar for the rhPTH (1–84) and placebo groups (P = 0.57) and mean levels remained above the upper limit of normal (≤ 250 mg/day) at week 24 of the REPLACE trial [19], palopegteriparatide showed a normalization of and significantly greater reduction in mean 24-h urine calcium excretion than placebo at week 26 of the PaTHway trial [7]. Results from the pharmacokinetics/pharmacodynamics (PK/PD) substudy of the phase 2 PaTH Forward trial demonstrated 24-h stability of serum and urine calcium levels consistent with steady release of active PTH upon daily dosing of palopegteriparatide in a population of adults with chronic hypoparathyroidism [23]. These findings suggest that palopegteriparatide may prevent the further declines in renal function that are characteristic of chronic hypoparathyroidism by eliminating the need for conventional therapy, reducing the periodic spikes in the filtered load of calcium and phosphate, and normalizing tubular handling of calcium and phosphate. While independence from conventional therapy and the ability of palopegteriparatide to provide physiological levels and functions of PTH likely both contribute to the phenomena described herein, additional studies are needed to elucidate the mechanism(s) whereby treatment with palopegteriparatide results in sustained increases in eGFR in adults with chronic hypoparathyroidism.

This post hoc, longitudinal analysis of the PaTHway trial is the first demonstration of significant improvements in renal function in individuals receiving PTH replacement therapy for chronic hypoparathyroidism. Potential limitations of this analysis, including its post hoc design, warrant consideration. The trial protocol specified the use of the MDRD equation, which is known to underestimate eGFR at higher values. Since all participants received palopegteriparatide during the open-label extension period of the trial there was no control group for comparison beyond the placebo arm through week 26. Inferences from the subgroup analysis examining the treatment effect of palopegteriparatide across baseline levels of renal function may be limited by the small number of participants with eGFR < 60 mL/min/1.73 m2 at baseline. The scope of this brief report does not include analysis of changes over time in conventional therapy doses, serum calcium, or other biochemical parameters with regard to impact on eGFR change. Further investigation of these parameters is warranted to permit a better understanding of the potential mechanisms of the observed results.

Conclusion

The results of this post hoc analysis of the pivotal phase 3 PaTHway trial confirm the safety and efficacy of palopegteriparatide in participants with established CKD and suggest that PTH replacement with palopegteriparatide and independence from conventional therapy may not only preserve but improve renal function in adults with chronic hypoparathyroidism.