A randomized first-in-human study of a novel growth hormone receptor peptide antagonist ALXN2420 in healthy subjects.

CONTEXT: Acromegaly is a rare disease typically caused by a growth hormone (GH) secreting pituitary adenoma. Somatostatin receptor ligand (SRL) monotherapy does not provide optimal control of circulating insulin-like growth factor-1 (IGF-1) levels in all patients with acromegaly. ALXN2420, a 16-amino acid peptide GH receptor antagonist (GHRA), is being developed in combination therapy in patients with acromegaly insufficiently controlled with SRLs.

OBJECTIVE

To evaluate the safety and tolerability (primary), pharmacokinetics and pharmacodynamics of ALXN2420 in healthy subjects.

DESIGN

Phase 1, randomized, double-blind, placebo-controlled single- (SAD) and 2-week multiple ascending dose (MAD) studies.

SETTING

Single center.

PATIENTS: Overall, 101 eligible and evaluable healthy subjects.

INTERVENTION: ALXN2420 or placebo.

MAIN OUTCOME MEASUREMENTS: Safety assessments, pharmacokinetic parameters, serum IGF-1 levels.

RESULTS

Subcutaneous injections of ALXN2420 up to 120 mg/day were well tolerated, with no safety concerns. Pharmacokinetic parameters increased dose proportionally. The terminal half-life was approximately 22 hours. ALXN2420 induced dose-related decreases in IGF-1 levels at doses ≥20 mg, with a more prolonged reduction at higher doses for up to 72 hours (SAD) and up to the end of treatment (MAD). Repeated daily ALXN2420 administration for 2 weeks suggested a cumulative effect compared to single administration. For ALXN2420 doses ≥40 mg, maximal mean changes from baseline versus placebo in IGF-1 levels ranged from approximately 20% to 30% (SAD) and 40% to 50% (MAD).

CONCLUSION

ALXN2420 doses of up to 120 mg/day appeared to be safe and substantially decreased IGF-1 levels in healthy subjects, thereby supporting further testing in patients with acromegaly.