Eftansomatropin alfa

Summary

Eftansomatropin alfa (MOD‑4023, Ngenla) is a recombinant human growth hormone (hGH) fused to the carboxy‑terminal peptide (CTP) of human chorionic gonadotropin. It is approved for prescription use as a long‑acting growth‑hormone replacement, administered subcutaneously once weekly to patients with growth‑hormone deficiency (GHD) in both adults and children.

Mechanism of Action

The CTP moiety prolongs circulating hGH by reducing renal clearance and slowing absorption after subcutaneous injection, extending the hormone’s half‑life five‑ to ten‑fold compared with daily recombinant hGH. The molecule retains the ability to bind the growth‑hormone receptor, albeit with lower affinity, triggering the JAK2‑STAT5 cascade that raises hepatic insulin‑like growth factor‑1 (IGF‑1) and IGFBP‑3, mediating growth and metabolic effects.

What the Research Shows

Phase‑1 pharmacokinetic studies in healthy Japanese and Caucasian adults showed dose‑dependent serum concentrations and maximal IGF‑1 response at 15 mg, with a favorable safety profile after a single subcutaneous dose. Pre‑clinical work demonstrated reduced in‑vitro potency but comparable exposure and IGF‑1 elevation after every‑5‑day dosing in rats and monkeys, with minimal adverse events. Phase‑2 trials in GHD adults (n=54) reported dose‑dependent IGF‑1 maintenance within normal ranges, good tolerability, and no serious safety signals. In children, weekly MOD‑4023 (0.25–0.66 mg/kg) over 12 months yielded a five‑ to ten‑fold longer half‑life, dose‑related IGF‑1 increases, and adequate catch‑up growth, with safety comparable to daily r‑hGH. Pharmacokinetic‑pharmacodynamic modeling identified day‑4 post‑dose sampling as optimal for estimating mean IGF‑1. A pivotal Phase‑3 trial is ongoing.

Reported Benefits

Weekly dosing may improve adherence compared with daily injections, reducing treatment burden. Clinical studies show that MOD‑4023 can maintain IGF‑1 within the normal range and support catch‑up growth in children, with efficacy approaching daily hGH at higher weekly doses. The extended half‑life allows fewer injections while delivering comparable systemic exposure, and the safety profile appears consistent with known GH‑related effects.

Limitations of the Evidence

In‑vitro receptor affinity and potency are lower than daily hGH, requiring higher weekly doses for equivalent effect. Evidence is limited to Phase‑1/2 trials with relatively small cohorts; long‑term outcomes and rare adverse events remain uncharacterized. Ethnic differences in absorption were observed in a single‑dose study. One adult dosing cohort was discontinued for insufficient efficacy, highlighting dose‑finding challenges. Ongoing Phase‑3 results are needed to confirm durability of benefit and safety.

Safety Considerations

Across studies, MOD‑4023 was well tolerated. Reported adverse events were typical of GH therapy (e.g., injection‑site reactions, transient edema, headache) and no serious adverse events occurred in the pediatric trial. Local tolerability was favorable after single‑dose administration in adults. Continuous monitoring for known GH‑related risks (e.g., intracranial hypertension, glucose intolerance) is advised, especially with long‑term use.

How It Is Administered

Eftansomatropin alfa is supplied for subcutaneous injection and is administered once weekly. Dosing in clinical studies ranged from 2.5 mg to 15 mg in adults and 0.25 mg/kg to 0.66 mg/kg in children, adjusted to achieve target IGF‑1 levels. The formulation is a CTP‑modified hGH fusion protein designed for prolonged systemic exposure.

Routes of Administration

Goals & Uses

• Adult growth hormone deficiency (investigational)EndocrinologyLow
• IGF-1 normalizationBiomarker / Surrogate EndpointHigh
• Improved treatment adherence via once-weekly dosingPatient Convenience / AdherenceHigh
• Treatment of pediatric growth hormone deficiency (pGHD)Endocrinology / GrowthHigh

Contraindications

• Active malignancyOncologyHighUse caution or avoid depending on agent and context
• Acute critical illnessCritical CareHigh
• Closed epiphyses (for growth promotion indication)Pediatric / SkeletalModerate
• Diabetic retinopathyOphthalmologyModerate
• Prader-Willi syndrome with severe obesity or respiratory impairmentGenetic SyndromeHigh
• Hypersensitivity to somatropin or excipientsAllergy / ImmunologyHigh

Adverse Effects

• Injection site reactionsLocalCommon
• HeadacheNeurologicCommonPain in the head or upper neck
• Fluid retention / edemaFluid / ElectrolyteUncommon
• Intracranial hypertensionNeurologicalRare
• HypothyroidismEndocrineUncommon
• Elevated IGF-1 levelsEndocrine / LaboratoryCommon

Drug Interactions

• GlucocorticoidsModerate
• Insulin / Oral antidiabeticsModerate
• Thyroid hormone replacementModerate
• CYP450 substrates (e.g., cyclosporine, sex hormones)Low

Population Constraints

• Patients with prior or active malignancyOncologyAbsolute
• PregnancyReproductive SafetyRelative
• AdultsAdult PopulationRelative
• Patients with diabetes mellitusMetabolicRelative
• Children under 3 years of agePediatricRelative

Regulatory Status

• European UnionApprovedApproved: Pediatric growth hormone deficiency (pGHD)EMA approved; marketed as Ngenla in the European Union.
• United StatesApprovedApproved: Pediatric growth hormone deficiency (pGHD) in patients 3 years and olderFDA approved June 2023; marketed as Ngenla by Pfizer/OPKO Health.
• United KingdomApprovedApproved: Pediatric growth hormone deficiency (pGHD)MHRA approved following EMA decision; available as Ngenla.

Approved by the FDA in June 2023 for pediatric patients 3 years and older with growth hormone deficiency. Also approved by the EMA. Developed by OPKO Health in partnership with Pfizer; marketed under the brand name Ngenla.

Evidence & Sources

• Pharmacokinetics, Pharmacodynamics, and Safety of a Long-Acting Human Growth Hormone (MOD-4023) in Healthy Japanese and Caucasian Adults
  Journal ArticleModerateKramer WG, et al.2018-01-01T00:00:00.000000Z
• In Vitro and in Vivo Characterization of MOD-4023, a Long-Acting Carboxy-Terminal Peptide (CTP)-Modified Human Growth Hormone
  Journal ArticleLowHershkovitz O, et al.2016-01-01T00:00:00.000000Z
• MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults
  Journal ArticleModerateStrasburger CJ, et al.2017-01-01T00:00:00.000000Z
• Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children
  Journal ArticleModerateFisher DM, et al.2017-01-01T00:00:00.000000Z
• Long-Acting C-Terminal Peptide-Modified hGH (MOD-4023): Results of a Safety and Dose-Finding Study in GHD Children
  Journal ArticleModerateZelinska N, et al.2017-01-01T00:00:00.000000Z

Frequently Asked Questions