NOT FOR HUMAN CONSUMPTION

Recombinant human IGF-1 (rhIGF-1) indicated for severe primary IGF-1 deficiency (SPIGFD) or GH-gene deletion with neutralizing anti-GH antibodies—conditions where endogenous IGF-1 remains low despite normal or high GH. It binds the IGF-1 receptor (IGF-1R) to drive somatic growth, protein synthesis, glucose uptake, and chondrocyte proliferation at the growth plate. It is prescription-only and distinct from GH: it replaces the end-hormone rather than stimulating its production.

Additional Benefits of Mecasermin Now Under Investigation

2. Molecular Mechanism of Action

2.1 Receptor Pharmacodynamics

• IGF-1R (tyrosine kinase) → PI3K–Akt–mTOR (protein synthesis, survival, glucose transport) and RAS–MAPK/ERK (proliferation/differentiation).

• Growth plate: Stimulates chondrocyte clonal expansion and hypertrophy, increasing endochondral ossification.

• Cross-talk: Partial activity at insulin receptor (IR) and IGF-1R/IR hybrids explains hypoglycemia risk.

2.2 Down-stream Biology

3. Pharmacokinetics

• Route: Subcutaneous, typically BID with meals/snack to mitigate hypoglycemia.

• Onset/half-life: Peak ~1–2 h; functional half-life ~5–8 h (age and binding-protein status influence).

• Binding proteins: Circulating IGF-1 is largely complexed with IGFBP-3/ALS, prolonging exposure; free fraction rises shortly post-dose.

• Titration: Start low and up-titrate every 1–2 weeks to max tolerated while monitoring pre- and post-prandial glucose.

4. Clinical Evidence (label populations)

4.1 Severe Primary IGF-1 Deficiency (SPIGFD)

• Height velocity rises markedly in year 1 and remains above baseline in years 2–4 when adherence and nutrition are adequate.

• Determinants of response: Younger start age, open epiphyses, absence of severe comorbid skeletal dysplasias, and consistent dosing.

4.2 GH-gene deletion with anti-GH antibodies

• rhIGF-1 circumvents blocked GH signaling to restore growth velocity; immunologic desensitization to GH is variably successful—IGF-1 provides a reliable bridge/alternative.

Evidence quality note: Supportive prospective registries, open-label extensions, and controlled pediatric datasets back efficacy in SPIGFD. Use in non-approved contexts remains investigational.

5. Emerging Clinical Interests

6. Safety and Tolerability

• Very important: Hypoglycemia—most common early/with missed food. Always dose with a meal/snack; educate family on glucose monitoring and glucagon rescue if indicated.

• Common: Injection-site reactions, headache, dizziness, otitis media, upper respiratory symptoms, arthralgia, edema, jaw discomfort (rapid mandibular growth), tonsillar/adenoidal hypertrophy (snoring/OSA symptoms).

• Oropharyngeal hypertrophy: Can cause sleep-disordered breathing; ENT evaluation if symptoms develop.

• Benign intracranial hypertension (rare): Headache, vomiting, visual changes—stop and evaluate.

• Scoliosis progression: Monitor during rapid growth.

• Neoplasia caution: IGF-1 is trophic; avoid in active or suspected malignancy. Long-term pediatric data have not shown a clear cancer signal in approved use, but vigilance is warranted.

• Allergy: Hypersensitivity is uncommon; monitor for urticaria/anaphylaxis.

• Drug interactions: Insulin/secretagogues increase hypoglycemia risk; glucocorticoids may blunt growth response; thyroid insufficiency must be corrected.

Comparative safety matrix (pediatrics)

7. Regulatory Landscape

• Status: Approved for SPIGFD and GH-gene deletion with neutralizing anti-GH antibodies (regional labels vary).

• Not approved for: Typical GH deficiency, idiopathic short stature, or performance enhancement.

• Distribution: Specialty pharmacy with risk-mitigation education for families.

8. Practical Use (clinic playbook)

• Confirm diagnosis: Low IGF-1 with normal/high GH, excluding secondary causes (malnutrition, hypothyroidism, chronic illness). Genetic testing for GHR/STAT5B/IGF1/IGFALS improves precision.

• Start low, go slow: Initiate BID SC with meals; titrate to effect/tolerability. Provide glucometer, hypoglycemia plan, and sick-day rules.

• Nutrition: Ensure adequate calories/protein, vitamin D/calcium; treat hypothyroidism or celiac disease if present.

• Monitoring: Height velocity, IGF-1/IGFBP-3, fasting/bedtime glucose, ENT (snoring/OSA), spine/hip pain, fundoscopy if headaches.

• When to pause/stop: Persistent hypoglycemia despite protocol, signs of intracranial hypertension, or neoplastic work-up.

• Transition planning: Reassess need as epiphyses close; focus on bone health and metabolic maintenance.

Selected References

• Journal of Clinical Endocrinology & Metabolism; Hormone Research in Paediatrics — Long-term outcomes of rhIGF-1 therapy in SPIGFD and anti-GH antibody states.

• Pediatric Research; Bone; JBMR — Skeletal and bone-mineral accrual during IGF-1 replacement.

• Diabetes; Metabolism — Insulin-sensitizing and lipid effects of IGF-1 in deficiency phenotypes.

• Endocrine Reviews; Clinical Endocrinology — Diagnostic algorithms for GH insensitivity and transition-age care.

• Hepatology; Liver International — Hepatic/IGF-axis interactions and labs during therapy.

• Psychoneuroendocrinology; Pediatrics — QoL and functional domains under replacement therapy.