The sustained-action PTH prodrug MBX 2109 was well tolerated with no unexpected, off-target safety issues, and its long half-life and flat exposure profile supports once-weekly administration for hypoparathyroidism treatment.
Key Findings
Results
MBX 2109 demonstrated an acceptable safety and tolerability profile across all dose groups with no severe or serious treatment-emergent adverse events.
Treatment-emergent adverse events (TEAEs) occurred in 50% to 88% of MBX 2109 groups compared to 25% of placebo participants.
No severe or serious TEAEs were observed in any MBX 2109 group.
Injection-site reaction was the most common treatment-related TEAE.
Study was a phase 1, randomized, double-blind, placebo-controlled, multiple ascending-dose trial (NCT05158335).
Results
MBX 2109 and its biologically active PTH peptide metabolite demonstrated long half-lives supporting once-weekly dosing.
Half-lives were 79 to 95 hours for MBX 2109 (the prodrug).
Half-lives were 184 to 213 hours for the fatty-acylated biologically active PTH peptide (the active metabolite).
The biologically active PTH agonist showed dose- and time-dependent exposure increases.
The flat exposure profile of the active metabolite was identified as supportive of once-weekly administration.
Methods
The study enrolled 40 healthy adult participants across four dose cohorts of MBX 2109 and placebo.
40 participants were randomly assigned in total (MBX 2109 n = 32, placebo n = 8).
Mean age was 43.3 years; 22.5% were female.
MBX 2109 was administered at doses of 200, 400, 600, and 900 μg (n = 8 per active dose group).
Each dose cohort had 2 placebo participants, with random assignment at 4:1 ratio (active:placebo).
Subcutaneous administration was given once weekly for 4 doses on days 1, 8, 15, and 22.
Background
MBX 2109 is a novel prodrug designed to yield a biologically active PTH peptide agonist (PTH[1-32] extended by a fatty acylated Lys33) as a long-acting PTH replacement therapy for hypoparathyroidism.
The active moiety is described as PTH[1-32], extended by a fatty acylated Lys33.
The prodrug mechanism is intended to provide sustained PTH activity.
Hypoparathyroidism is characterized by PTH deficiency and impaired mineral metabolism.
MBX 2109 is being developed as a once-weekly subcutaneous therapy.
Methods
Pharmacodynamic effects were assessed as key secondary endpoints alongside pharmacokinetics in this first-in-human study.
Primary endpoint was safety and tolerability.
Key secondary endpoints included pharmacokinetics (PK) and pharmacodynamics (PD).
MBX 2109 doses were identified for use in future studies based on the PK/PD and safety findings.
This was reported as a phase 1, first-in-human study.