Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial

Abstract

Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism. The double-blind, placebo-controlled, 26-week, phase 3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism individuals with the investigational drug TransCon PTH (palopegteriparatide). Participants (n = 84) were randomized 3:1 to once-daily TransCon PTH (initially 18 μg/d) or placebo, both co-administered with conventional therapy. The study drug and conventional therapy were titrated according to a dosing algorithm guided by serum calcium. The composite primary efficacy endpoint was the proportion of participants at week 26 who achieved normal albumin-adjusted serum calcium levels (8.3-10.6 mg/dL), independence from conventional therapy (requiring no active vitamin D and ≤600 mg/d of calcium), and no increase in study drug over 4 weeks before week 26. Other outcomes of interest included health-related quality of life measured by the 36-Item Short Form Survey (SF-36), hypoparathyroidism-related symptoms, functioning, and well-being measured by the Hypoparathyroidism Patient Experience Scale (HPES), and urinary calcium excretion. At week 26, 79% (48/61) of participants treated with TransCon PTH versus 5% (1/21) wiplacebo met the composite primary efficacy endpoint (p < 0.0001). TransCon PTH treatment demonstrated a significant improvement in all key secondary endpoint HPES domain scores (all p < 0.01) and the SF-36 Physical Functioning subscale score (p = 0.0347) compared with placebo. Additionally, 93% (57/61) of participants treated with TransCon PTH achieved independence from conventional therapy. TransCon PTH treatment normalized mean 24-hour urine calcium. Overall, 82% (50/61) treated with TransCon PTH and 100% (21/21) wiplacebo experienced adverse events; most were mild (46%) or moderate (46%). No study drug-related withdrawals occurred. In conclusion, TransCon PTH maintained normocalcemia while permitting independence from conventional therapy and was well-tolerated in individuals with hypoparathyroidism. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Trial registration: ClinicalTrials.gov NCT04009291.

Keywords: CLINICAL TRIALS; DISORDERS OF CALCIUM/PHOSPHATE; HORMONE REPLACEMENT; PARATHYROID-RELATED DISORDERS; PTH/VIT D/FGF23.

Fig. 1

Patient disposition. A total of 106 participants were screened, and 84 met eligibility criteria, were enrolled in the trial, and randomized to treatment. Two participants randomized to TransCon PTH discontinued the trial before receiving treatment: one withdrew consent, and one withdrew due to thyroid cancer recurrence. Sixty‐one participants in the TransCon PTH and 21 participants in the placebo group received ≥1 blinded treatment and comprised the intent‐to‐treat population. During the trial, one participant in the TransCon PTH group experienced a fatal cardiac arrest (unrelated to the study drug), and 2 withdrew from the placebo group: one withdrew consent, and one withdrew due to breast cancer. A total of 79 participants completed the blinded treatment through week 26.

Fig. 2

Elemental calcium supplement dose with TransCon PTH treatment. Treatment with TransCon PTH resulted in a greater reduction in mean daily calcium dose than placebo as early as 4 weeks (p = 0.0003) and through 26 weeks (p = 0.0003). After 4 weeks of treatment with TransCon PTH, elemental calcium intake decreased from a baseline mean (SD) of 1748.0 (903.9) mg/d to a mean (SD) dose of 548.8 (832.7) mg/d, which continued to decrease throughout the trial to a mean (SD) dose of 274.2 (1371.8) mg/d at week 26. Per trial protocol, participants were permitted to take calcium ≤600 mg/d as a nutritional supplement, if needed, to meet the recommended dietary intake of calcium. Negative error bars (SD) are not displayed for values less than zero.

Fig. 3

Active vitamin D supplement dose with TransCon PTH treatment. Per trial protocol, all participants decreased their active vitamin D dose by 33% to 50% (eg, by skipping the second dose of the day if taking 2 times daily (BID), skipping the final dose of the day if taking 3 times daily (TID), or reducing a once‐daily dose of alfacalcidol ≥1.0 μg by 50% (≥0.5 μg) at the start of the blinded treatment period. Subsequent dose decreases or discontinuations were done according to a predefined protocol. Within 4 weeks, the majority of participants treated with TransCon PTH discontinued active vitamin D. Mean doses of active vitamin D supplements were calculated from actual micrograms prescribed and are not adjusted for relative potency of calcitriol versus alfacalcidol. The difference in least squares (LS) means between TransCon PTH and placebo groups was statistically significant at all time points (p < 0.0001). Negative error bars (SD) are not displayed for values less than zero.

Fig. 4

Albumin‐adjusted serum calcium with TransCon PTH treatment. In the TransCon PTH group, mean serum calcium values remained within the normal range at all study visits through week 26. Baseline mean serum calcium was 8.8 mg/dL (2.2 mmol/L) and 8.6 mg/dL (2.15 mmol/L) for TransCon PTH and placebo, respectively, and 8.9 mg/dL (2.22 mmol/L) and 8.2 mg/dL (2.05 mmol/L), respectively, at week 26. Normal range for serum calcium = 8.3–10.6 mg/dL (2.07–2.64 mmol/L).

Fig. 5

Treatment effect of TransCon PTH on the hypoparathyroidism patient experience scale (HPES).^aThe HPES is a psychometrically validated, disease‐specific measure specifically designed to assess the symptoms and impact associated with hypoparathyroidism. A higher HPES score indicates greater symptom frequency or impact. ^bThe p values are from ANCOVA models testing the difference in change from baseline at week 26 between TransCon PTH and placebo, with etiology of hypoparathyroidism as fixed effects and baseline HPES domain scores as covariates. TransCon PTH treatment demonstrated a significant improvement compared with placebo at week 26 in HPES‐Symptom domain scores: (A) physical (p = 0.0038) and (B) cognitive (p = 0.0055); and HPES‐Impact domain scores: (C) physical functioning (p = 0.0046) and (D) daily life (p = 0.0061). Lower HPES scores indicate improvement. Negative error bars (SD) are not displayed for values less than zero.

Fig. 6

Treatment effect of TransCon PTH on general health, 36‐Item Short Form Survey (SF‐36). ^a36‐Item Short Form Survey (SF‐36) subscale score, a patient‐reported survey that serves as a general measure of well‐being. In the SF‐36 subscale, lower scores are associated with a greater disease burden; increases in scores indicate improvement. ^bThe dashed lines indicate the upper (53) and lower (47) T‐score bounds for the US general population's average level of functioning, with scores below 47 indicating impairment. Source: Maruish ME (editor). User's Manual for the SF‐36v2 Health Survey (3rd ed.). Lincoln, RI: Quality Metric Incorporated.

Fig. 7

Twenty four‐hour urine calcium with TransCon PTH treatment. Box plot of 24‐hour urine calcium. Within each box, horizontal lines denote median values and the square (TransCon PTH), and circle (placebo) denote mean values; boxes extend from the 25th to the 75th percentile of each treatment group's distribution of values; vertical extending lines denote adjacent values within 1.5 interquartile range of the 25th and 75th percentile of each group; dots outside the box denote data points outside the range of adjacent values. Mean 24‐hour urine calcium values decreased from 390 mg/24 h at baseline to 220 mg/24 h at week 26 in participants treated with TransCon PTH, and from 329 to 292 mg/24 h in participants who received placebo. The mean change from baseline was statistically significant in the TransCon PTH group (p < 0.0001) but not in the placebo group (p = 0.24). An ANCOVA model testing the difference in change from baseline at week 26 between TransCon PTH and placebo, with etiology of hypoparathyroidism as fixed effects and baseline urine calcium excretion value as a covariate showed a significant difference between groups (p = 0.0085). ULN = upper limit of normal.