Skytrofa - Drug Monograph

Introduction

Skytrofa (lonapegsomatropin) is a novel long-acting prodrug of somatropin approved for the treatment of pediatric growth hormone deficiency (GHD). This once-weekly subcutaneous injection represents a significant advancement in growth hormone therapy by reducing administration frequency from daily to weekly, potentially improving treatment adherence and quality of life for patients and caregivers.

Mechanism of Action

Skytrofa utilizes a proprietary TransCon technology that temporarily links somatropin to an inert carrier molecule via a self-cleaving linker. Following subcutaneous administration, the linker undergoes predictable, pH-dependent hydrolysis at physiological conditions, resulting in sustained release of unmodified somatropin over approximately one week. The released somatropin binds to growth hormone receptors, stimulating insulin-like growth factor 1 (IGF-1) production, which promotes linear growth, protein synthesis, and metabolic effects.

Indications

Skytrofa is indicated for the treatment of pediatric patients weighing at least 11.5 kg who have growth failure due to inadequate secretion of endogenous growth hormone.

Dosage and Administration

• Initial dosing: 0.24 mg/kg body weight administered subcutaneously once weekly
• Titration: Dose may be adjusted based on clinical response and IGF-1 levels
• Administration: Subcutaneous injection in the abdomen, thigh, or upper arm
• Reconstitution: Requires reconstitution with provided diluent
• Special populations: No dosage adjustment required for renal or hepatic impairment
• Missed dose: Administer as soon as possible if within 3 days of scheduled dose

Pharmacokinetics

• Absorption: Slow, sustained release of somatropin over approximately 168 hours
• Distribution: Released somatropin distributes similarly to endogenous growth hormone
• Metabolism: Hepatic metabolism via proteolytic cleavage
• Elimination: Renal clearance with half-life of approximately 25 hours for released somatropin
• Bioavailability: Complete bioavailability of released somatropin

Contraindications

• Hypersensitivity to lonapegsomatropin or any component of the formulation
• Active malignancy
• Active proliferative or severe non-proliferative diabetic retinopathy
• Acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure
• Prader-Willi syndrome who are severely obese or have severe respiratory impairment
• Closed epiphyses

Warnings and Precautions

• Neoplasms: Monitor patients with a history of malignancy for recurrence
• Glucose intolerance: May decrease insulin sensitivity; monitor glucose levels
• Intracranial hypertension: Funduscopic examination recommended if symptoms occur
• Fluid retention: May occur during initial treatment phase
• Hypothyroidism: Undiagnosed/untreated hypothyroidism may impair response
• Slipped capital femoral epiphysis: Evaluate patients with limp or hip/knee pain
• Pancreatitis: Consider pancreatitis in patients with abdominal pain
• Lipoatrophy: Rotate injection sites to prevent tissue atrophy

Drug Interactions

• Glucocorticoids: May inhibit growth promotion; adjust glucocorticoid dosage if needed
• Cytochrome P450 substrates: Somatropin may alter metabolism of drugs metabolized by CYP450 enzymes
• Oral estrogen: May reduce serum IGF-1 response
• Insulin: May require adjustment of insulin doses

Adverse Effects

• Injection site reactions (32%)
• Viral infection (19%)
• Pyrexia (17%)
• Headache (13%)
• Cough (8%)
• Abdominal pain (7%)
• Vomiting (7%)

• Intracranial hypertension
• Hypersensitivity reactions
• Slipped capital femoral epiphysis
• Pancreatitis
• Glucose intolerance
• Fluid retention

Monitoring Parameters

• Height and growth velocity every 3-6 months
• IGF-1 levels at 4-week intervals after dose changes, then every 6-12 months
• Thyroid function tests annually
• Blood glucose levels as clinically indicated
• Funduscopic examination if symptoms of intracranial hypertension occur
• Hip examination if limp or hip/knee pain reported
• Injection sites for reactions or lipoatrophy

Patient Education

• Demonstrate proper injection technique and rotation of injection sites
• Explain importance of consistent weekly dosing
• Instruct on proper storage and reconstitution procedures
• Educate about signs of hyperglycemia (increased thirst/urination)
• Discuss symptoms requiring immediate medical attention (severe headache, visual changes, hip/knee pain)
• Emphasize importance of regular follow-up appointments
• Provide guidance on missed dose management
• Discuss proper disposal of used needles and syringes

References

1. FDA Approval Package: Skytrofa (lonapegsomatropin). US Food and Drug Administration. 2021. 2. Deal C, et al. Efficacy and safety of weekly somatrogon vs daily somatropin in children with growth hormone deficiency: A phase 3 study. J Clin Endocrinol Metab. 2022;107(2):e578-e587. 3. Savendahl L, et al. Long-acting growth hormone preparations and their use in children with growth hormone deficiency. Horm Res Paediatr. 2023;96(1):1-13. 4. Skytrofa [package insert]. San Diego, CA: Ascendis Pharma; 2023. 5. Cleland JL, et al. The TransCon technology platform: A new approach to long-acting therapeutics. Drug Discov Today. 2022;27(2):513-525. 6. ClinicalTrials.gov. Study of TransCon hGH vs. Daily hGH in Children With Growth Hormone Deficiency (GHD). Identifier: NCT02903004.