A randomized double‐blind placebo‐controlled first‐in‐human phase 1 trial of TransCon PTH in healthy adults

Karpf, David B.; Pihl, Susanne; Mourya, Sanchita; Mortensen, Eva; Kovoor, Eshwari; Markova, Denka; Leff, Jonathan A.

Affiliations

¹Ascendis Pharma, Inc. Palo Alto CA USA

²Ascendis Pharma A/S Hellerup Denmark

Abstract and keywords

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.

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

Links

DOI: 10.1002/jbmr.4016

PubMed: 32212275

WoS: 000526161900001

History

Received: 2019-10-16

Revised: 2020-03-10

Accepted: 2020-03-15

Online: 2020-04-16

Cited Works (1)

Year	Entry
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Cited By (6)

Year	Entry
2022	Roszko KL, Smith LMS, Sridhar AV, Roberts MS, Hartley IR, Gafni RI, Collins MT, Fox JC, Nemeth EF. Autosomal dominant hypocalcemia type 1: a systematic review. J Bone Miner Res. October 2022;37(10):1926-1935.
2022	Khan AA, Bilezikian JP, Brandi ML, Clarke BL, Gittoes NJ, Pasieka JL, Rejnmark L, Shoback DM, Potts JT, Guyatt GH, Mannstadt M. Evaluation and management of hypoparathyroidism summary statement and guidelines from the second international workshop. J Bone Miner Res. December 2022;37(12):2568-2585.
2022	Yao L, Li J, Li M, Lin C, Hui X, Tamilselvan D, Kandi M, Sreekanta A, Makhdami N, Ali DS, Dandurand K, Yang K, Bilezikian JP, Brandi ML, Clarke BL, Mannstadt M, Rejnmark L, Khan AA, Guyatt G. Parathyroid hormone therapy for managing chronic hypoparathyroidism: a systematic review and meta-analysis. J Bone Miner Res. December 2022;37(12):2654-2662.
2022	Khan AA, Guyatt G, Ali DS, Bilezikian JP, Collins MT, Dandurand K, Mannstadt M, Murphy D, M'Hiri I, Rubin MR, Sanders R, Shrayyef M, Siggelkow H, Tabacco G, Tay Y-KD, Van Uum S, Vokes T, Winer KK, Yao L, Rejnmark L. Management of hypoparathyroidism. J Bone Miner Res. December 2022;37(12):2663-2677.
2023	Khan AA, Rubin MR, Schwarz P, Vokes T, Shoback DM, Gagnon C, Palermo A, Marcocci C, Clarke BL, Abbott LG, Hofbauer LC, Kohlmeier L, Pihl S, An X, Eng WF, Smith AR, Ukena J, Sibley CT, Shu AD, Rejnmark L. Efficacy and safety of parathyroid hormone replacement with TransCon PTH in hypoparathyroidism: 26-week results from the phase 3 PaTHway trial. J Bone Miner Res. January 2023;38(1):14-25.
2023	Agarwal S, McMahon DJ, Chen J, Brossfield AV, Fernando J, Bilezikian JP, Cusano NE, Rubin MR. The clinical and skeletal effects of long-term therapy of hypoparathyroidism with rhPTH(1-84). J Bone Miner Res. April 2023;38(4):480-492.