A Randomized Double-Blind Placebo-Controlled First-In-Human Phase 1 Trial of TransCon PTH in Healthy Adults

Abstract

TransCon PTH is a sustained-release, essentially inactive prodrug transiently bound to an inert carrier, designed to release PTH(1-34), and in development for hypoparathyroidism (HP). This phase 1, randomized, placebo-controlled, single and multiple ascending dose (SAD and MAD, respectively) trial evaluated safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of TransCon PTH in healthy adults. SAD and MAD cohorts consisted of 10 subjects (eight active, two placebo) who received up to seven single or six multiple ascending doses of TransCon PTH, respectively. TransCon PTH doses ranged from 3.5 to 124 μg PTH(1-34) for the SAD cohorts and 3.5 to 24 μg PTH(1-34)/day for the MAD cohorts. The primary PK endpoint was Free PTH. The PD endpoints included albumin adjusted serum calcium (sCa), fractional excretion of calcium (FECa), intact endogenous PTH(1-84), bone turnover markers, renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR), serum phosphate (sP) and magnesium, and 1,25 dihydroxyvitamin D. TransCon PTH was generally well tolerated; there were no drug-related serious adverse events (SAEs), and all AEs were transient in nature. Free PTH demonstrated an effective half-life of approximately 60 hours and a dose-dependent, sustained exposure with an infusion-like profile within the calculated physiologic range for active PTH at steady-state. Albumin-adjusted sCa demonstrated a dose-dependent, sustained response with complete control of FECa despite modest hypercalcemia at higher doses. Renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR) showed a dose-dependent decrease, resulting in a dose-dependent decrease in sP. TransCon PTH administered daily for 10 days showed no increase in the osteoblastic bone formation markers, serum bone-specific alkaline phosphatase (BSAP) or P1NP, or the osteoclastic bone resorption marker, urine NTx, but modestly and transiently increased the osteoclast marker, serum CTx. These phase 1 data support TransCon PTH as a daily replacement therapy for HP providing physiological levels of PTH 24 hours per day and advancement into phase 2 clinical development. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Keywords: CLINICAL TRIALS; DISORDERS OF CALCIUM/PHOSPHATE METABOLISM; HYPOPARATHYROIDISM; LONG ACTING PTH; PTH; THERAPEUTICS.

Figure 1

TransCon PTH, a long‐acting prodrug consisting of a parent drug, PTH(1‐34), transiently bound to a carrier via a linker that is autocleaved, releasing active PTH(1‐34) (and PTH(1‐33)).

Figure 2

The mean ± SE plasma concentration of Free PTH (pg/mL) after (A) single or (B) multiple doses (at day 10) of TransCon PTH. Note, the calculated normal range for PTH(1‐34), 4 to 26 pg/mL, was derived from 40% of the molecular weight of PTH(1‐84). LLN = lower limit of normal.

Figure 3

Mean ± SE change in plasma concentration of albumin‐adjusted serum calcium (mg/dL), following (A) a single dose or (B) daily doses for 10 days of TransCon PTH (n = 8/group). (Note: “Baseline” includes mean predose values on day 1 whereas “day 1” includes mean postdose values on day 1.) PTH = parathyroid hormone.

Figure 4

Spot FECa with daily doses of TransCon PTH (n = 8/group) for 10 days. ULN = upper limit of normal.

Figure 5

Box plots of the change of serum phosphate from baseline with daily doses of TransCon PTH for 10 days (values reflect the change from baseline over days 8 to 10).

Figure 6

Phosphaturic effect with daily doses of TransCon PTH for 10 days (box plots reflect the change from baseline over days 8 to 10).

Figure 7

Suppression of intact endogenous PTH(1‐84) with daily doses of TransCon PTH (n = 8/group) for 10 days (the dashed line indicates the LLOQ; ie, 3 pg/mL). LLOQ = lower limit of quantification.

Figure 8

Mean ± SE percentage change from baseline in serum BSAP with daily doses of TransCon PTH (n = 8/group) for 10 days.

Figure 9

Mean ± SE percentage change from baseline in serum CTx with daily doses of TransCon PTH (n = 8/group) for 10 days.