Safety, pharmacokinetics, and pharmacodynamics of efzimfotase alfa, a second-generation enzyme replacement therapy: phase 1, dose-escalation study in adults with hypophosphatasia.

Autor:	Dahir KM; Program for Metabolic Bone Disorders, Vanderbilt University Medical Center, Nashville, TN 37232-8148, United States., Shannon A; Development, Regulatory and Safety, Alexion, AstraZeneca Rare Disease, Boston, MA 02210, United States., Dunn D; Development, Regulatory and Safety, Alexion, AstraZeneca Rare Disease, Boston, MA 02210, United States., Voegtli W; Development, Regulatory and Safety, Alexion, AstraZeneca Rare Disease, Boston, MA 02210, United States., Dong Q; Development, Regulatory and Safety, Alexion, AstraZeneca Rare Disease, Boston, MA 02210, United States., Hasan J; Development, Regulatory and Safety, Alexion, AstraZeneca Rare Disease, Boston, MA 02210, United States., Pradhan R; Development, Regulatory and Safety, Alexion, AstraZeneca Rare Disease, Boston, MA 02210, United States., Pelto R; Bioanalytical and Biomarker Development, Alexion, AstraZeneca Rare Disease, New Haven, CT 06510, United States., Pan WJ; Development, Regulatory and Safety, Alexion, AstraZeneca Rare Disease, Boston, MA 02210, United States.
Jazyk:	angličtina
Zdroj:	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2024 Sep 26; Vol. 39 (10), pp. 1412-1423.
DOI:	10.1093/jbmr/zjae128
Abstrakt:	Hypophosphatasia (HPP) is a rare, inherited metabolic disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Efzimfotase alfa (ALXN1850) is a second-generation TNSALP enzyme replacement therapy in development for HPP. This first-in-human open-label, dose-escalating phase 1 trial evaluated efzimfotase alfa safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. Fifteen adults (5/cohort) with HPP received efzimfotase alfa in doses of 15 mg (cohort 1), 45 mg (cohort 2), or 90 mg (cohort 3) as one intravenous (i.v.) dose followed by 3 weekly subcutaneous (s.c.) doses. The primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics of ALP substrates known to be biomarkers of disease (inorganic pyrophosphate [PPi] and pyridoxal 5'-phosphate [PLP]) and immunogenicity. Treatment-emergent adverse events (TEAEs) occurred in 12 (80%) participants. Eight (53%) participants had injection site reactions (ISRs), observed after 10 of 41 (24%) s.c. injections. Most ISR TEAEs were mild and resolved within 1-2 d. Peak and total exposures of efzimfotase alfa increased in a greater-than-dose proportional manner over the range of 15-90 mg after i.v. and s.c. dosing. The arithmetic mean elimination half-life was approximately 6 d; absolute bioavailability was 28.6%-36.8% over the s.c. dose range of 15-90 mg. Dose-dependent reductions in plasma concentrations of PPi and PLP relative to baseline reached nadir in the first week after i.v. dosing and were sustained for 3-4 wk after the last s.c. dose. Four (27%) participants tested positive for antidrug antibodies (ADAs), 3 of whom were ADA positive before the first dose of efzimfotase alfa. ADAs had no apparent effect on efzimfotase alfa pharmacokinetics/pharmacodynamics. No participants had neutralizing antibodies. Efzimfotase alfa demonstrated acceptable safety, tolerability, and pharmacokinetic profiles and was associated with sustained reductions in biomarkers of disease in adults with HPP, supporting further evaluation in adult and pediatric patients. Registration: ClinicalTrials.gov NCT04980248 (https://clinicaltrials.gov/study/NCT04980248). (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)
Databáze:	MEDLINE
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