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A randomized first-in-human study of a novel growth hormone receptor peptide antagonist ALXN2420 in healthy subjects
Soraya Allas1, Guillaume Ravel1, Colm Farrell2
1Amolyt Pharma, Ecully 69130, France.
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.
Insights
The novel drug ALXN2420, a growth hormone receptor antagonist (GHRA), demonstrated safety and dose-dependent reductions in insulin-like growth factor-1 (IGF-1) levels in healthy subjects. These findings support its potential use in acromegaly treatment.
Area of Science:
- Endocrinology
- Pharmacology
- Clinical Trials
Background:
- Acromegaly, a rare disorder, results from excess growth hormone (GH) and often requires combination therapy beyond somatostatin receptor ligands (SRLs) for optimal control.
- ALXN2420 is an investigational growth hormone receptor antagonist (GHRA) designed to improve treatment outcomes for acromegaly patients inadequately managed by SRLs.
Purpose of the Study:
- Evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ALXN2420 in healthy individuals.
- Assess the dose-related effects of ALXN2420 on insulin-like growth factor-1 (IGF-1) levels.
Main Methods:
- Phase 1, randomized, double-blind, placebo-controlled studies involving single ascending doses (SAD) and 2-week multiple ascending doses (MAD).
- 101 healthy subjects received subcutaneous injections of ALXN2420 or placebo.
- Key assessments included safety monitoring, pharmacokinetic profiling, and measurement of serum IGF-1 levels.
Main Results:
- ALXN2420 was well-tolerated up to 120 mg/day with no safety concerns identified.
- Pharmacokinetics demonstrated dose proportionality, with a terminal half-life of approximately 22 hours.
- Significant, dose-related reductions in IGF-1 levels were observed starting at 20 mg, with prolonged effects at higher doses and evidence of cumulative effects with repeated administration.
Conclusions:
- ALXN2420 up to 120 mg/day was found to be safe and effectively lowered IGF-1 levels in healthy subjects.
- The observed safety profile and pharmacodynamic effects support further clinical investigation of ALXN2420 in acromegaly patients.
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