Key Clinical Summary: Individualized IGF-I Monitoring Strategies for GH and LAGH Therapy

This is a micro-learning module summary from the GHD Education program which you can find here.

Before participating please read our CME and disclosure information which can be found here. This program was supported by an independent medical education grant from Novo Nordisk. This content is intended for US Healthcare Professionals only.

Introduction

Daily recombinant human growth hormone (rhGH) has been a safe and effective therapy for pediatric Growth Hormone Deficiency (GHD) for decades. However, its efficacy is often limited by a significant real-world challenge: non-adherence. The burden of daily injections, especially for adolescents and families with complex needs, can lead to missed doses in a significant proportion of patients. This suboptimal adherence is associated with reduced linear growth and a failure to achieve target adult height.

Once-weekly, long-acting growth hormone (LAGH) formulations were developed to address this adherence barrier, with the expectation of improving overall treatment outcomes. While Phase 3 trials have confirmed their efficacy, these novel therapies introduce a paradigm shift in clinical management, demanding new, individualized strategies for monitoring and dose adjustment.

From Daily Injections to Once-Weekly Formulations

Several LAGH products are now approved, each utilizing a different technology to prolong its half-life:

• Lonapegsomatropin
• Somapacitan
• Somatrogon

Clinical trials have demonstrated that these once-weekly therapies are non-inferior to daily rhGH in achieving annualized height velocity (AHV) over 52 weeks, with comparable safety profiles.

The Paradigm Shift in Monitoring: Understanding IGF-I Fluctuation

The primary challenge in transitioning from daily GH to LAGH lies in monitoring Insulin-Like Growth Factor I (IGF-I).

• With Daily GH: IGF-I levels remain relatively stable throughout the day and week. Therefore, the timing of a blood draw for IGF-I monitoring is not critical.
• With LAGH: A single weekly injection creates a pronounced pharmacodynamic profile. IGF-I levels fluctuate, typically peaking around day 2-3 after the injection and reaching a trough just before the next dose on day 7.

Key Takeaway: A single, random IGF-I measurement in a patient on LAGH is uninterpretable without knowing the precise time elapsed since the last injection. The clinical goal is to estimate the average weekly IGF-I, which is believed to be the most relevant marker for both efficacy and safety.

Practical Strategies for IGF-I Monitoring and Dosing

To make data-driven decisions, clinicians must adopt a new, time-dependent approach to IGF-I interpretation.

• The Ideal Timing: For all major LAGH products, drawing a blood sample approximately 4 days after the injection provides an IGF-I value that closely reflects the average weekly level, often requiring no adjustment.
• Adjusting for Non-Ideal Timing: When a sample cannot be drawn on day 4, its value must be adjusted using drug-specific correction factors or lookup tables to estimate the average weekly IGF-I.
• An IGF-I level drawn at peak (Days 2-3) will be higher than the weekly average and must be adjusted downwards.
• An IGF-I level drawn at trough (Days 0, 1, 6, 7) will be lower than the weekly average and must be adjusted upwards.

Patient Selection and Long-Term Considerations

• Ideal Candidates: Children at high risk for non-adherence are excellent candidates for LAGH. This includes adolescents, patients with complex medical or social situations, and those with previously demonstrated poor adherence to daily therapy.
• Populations Requiring Caution:
• Children with severe GHD and a history of hypoglycemia may be at risk during the trough period of LAGH therapy.
• The safety and efficacy in cancer survivors have not yet been established, as this group was excluded from the pivotal clinical trials.
• The Need for Long-Term Data: While LAGH therapy is non-inferior in the short term, the ultimate goal is to achieve better final height outcomes by improving adherence. Long-term surveillance registries, such as the global
• GloBE-Reg initiative, are essential to confirm these long-term benefits and to monitor for any unforeseen safety signals related to prolonged exposure to unphysiological GH profiles (e.g., metabolic, cardiovascular, or neoplasia risk).

Conclusion

Long-acting GH therapies represent a significant clinical advance, directly addressing the critical issue of non-adherence that has long hampered the success of daily GH treatment. However, their adoption requires clinicians to embrace a new monitoring strategy. Moving beyond single-point IGF-I values and learning to use time-and-drug-specific adjustments to estimate the average weekly IGF-I is crucial for individualizing therapy and optimizing patient outcomes. Continued participation in long-term safety and efficacy registries will be vital to fully establish the role of LAGH in the management of GHD.