Growth hormone (GH) is a fundamental regulator of human growth and development. Recombinant human growth hormone (rhGH) therapies are widely indicated for short stature resulting from various etiologies, most notably pediatric growth hormone deficiency (GHD). Since the earliest rhGH formulations required daily subcutaneous injections, patient compliance emerged as a primary clinical challenge. The development of weekly long-acting growth hormone (LAGH) has significantly improved treatment adherence and the overall patient experience—reducing the injection burden by over 300 needles per year and alleviating the psychological distress associated with daily administration.

One of the key goals in developing long-acting drugs is to prolong half-life, but a longer half-life is not always better. Instead, it must be tailored to the specific mechanism of action (MoA) to achieve an optimal therapeutic window. The development of LAGH adheres strictly to these pharmacological principles.

One of the most effective strategies for achieving sustained release is Polyethylene Glycol (PEG) modification, or PEGylation. By conjugating the molecule with PEG, the hydrodynamic volume of the drug increases, which slows its metabolic degradation and renal clearance. Compared to standard rhGH, PEGylated LAGH exhibits enhanced systemic stability and increased resistance to proteolytic degradation. It also possesses the potential to mitigate or entirely avert immunogenicity under specific conditions and may contribute to a significant reduction in overall toxicity.

PEGylation has been employed in drug development for nearly 50 years, and its safety has been extensively validated in clinical settings. 

PEGylated Long-Acting Growth Hormones Approved in China

China has approved three PEGylated LAGH therapies. These therapies represent a shift from daily administration to weekly dosing, optimizing both pharmacokinetic profiles and patient adherence.

Jintrolong® (PEG-rhGH)

In 2014, GeneScience Pharmaceuticals (GenSci) received marketing authorization for Jintrolong, making it the world’s first PEGylated recombinant human growth hormone (rhGH) formulation to reach the market. Its approval effectively ended the era of mandatory daily injections for many patients.

Molecular Design: It employs a U-shaped branched N-terminal PEGylated rhGH (UPEG-rhGH) platform.

Pharmacokinetics: This structural modification yields a mean half-life of approximately 31 hours, facilitating a once-weekly dosing schedule.

Pegpesen® (inpegsomatropin)

In May 2025, Amoytop Biotech received approval for Pegpesen, indicated for growth failure due to pediatric growth hormone deficiency (GHD) in children aged 3 years and older.

Molecular Design: Pegpesen consists of a 40-kDa Y-shaped branched PEG chain conjugated to the alpha-amino group in the epsilon-amino group of lysine in the side chain of rhGH.

Pharmacokinetics: This specific conjugation results in a mean half-life ranging from 65 to 120 hours. This represents an extension of nearly 20 times the half-life of conventional daily rhGH, offering a highly stable systemic presence.

Skytrofa (Lonapegsomatropin)

On January 26, 2026, the National Medical Products Administration (NMPA) officially approved Lonapegsomatropin (Skytrofa) for the treatment of pediatric GHD in China. Developed using the innovative TransCon™ platform, it represents a "next-generation" approach to long-acting therapies. 

Molecular Design: Skytrofa comprises the parent somatropin molecule (22 kDa) conjugated to a methoxypolyethylene glycol (mPEG) carrier (4 x 10kDa) through a proprietary TransCon Linker. The total molecular weight of the prodrug is approximately 63 kDa.

Pharmacokinetics: The linker is designed to release unmodified somatropin at a controlled, physiological rate, resulting in a mean (±SD) observed half-life of 30.7 (±12.7) hours.

Structural Variations in PEG Architectures: Linear, Y-shape, and U-shape

The architecture of the PEG moiety plays a critical role in determining pharmacokinetic behavior and clinical performance of the LAGH therapies.

Linear PEG

Linear PEG molecules consist of a single-chain structure extending in a single direction from the conjugation site. This results in a linear spatial conformation, creating a relatively narrow protective shield across the protein’s surface. While effective for basic half-life extension, its spatial coverage is less comprehensive than branched alternatives.

Y-shape vs. U-shape

From a structural perspective, although Y-shaped and U-shaped PEGs share certain configurational similarities, they are not architecturally identical (Figure 1). These subtle geometric variances can significantly influence pharmacokinetic (PK) profiles and performance in clinical applications.

Figure 1. U-shape & Y-shape PEGs

U-shaped PEGs typically utilize carbamate linkages to tether dual 20 kDa PEG chains. The symmetry of using identical chemical bonds for both chains contributes to high structural stability, which in turn facilitates a predictable and consistent pharmacokinetic profile. Publicly available data for U-PEG-rhGH (such as Jintrolong) indicates an elimination half-life of 32.19±4.58 hours. Following consecutive weekly administration, the drug shows no significant systemic accumulation (RAUC≈1.03) allowing for clear and manageable dose titration in clinical practice.

In contrast, existing literature regarding Y-PEG-rhGH (such as Pegpesen) reveals significantly higher inter-individual variability. The observed half-life exhibits a broad dispersion, ranging from approximately 53.4 to 200 hours. This wider range suggests that drug clearance rates may vary substantially between patients, necessitating more intensive individualized monitoring to ensure therapeutic efficacy and safety.

All in all, the choice of PEG architecture is a balancing act between achieving the desired duration of action and maintaining a manageable, safe pharmacokinetic profile across a diverse patient population.

Conclusion

The evolution of growth hormone therapy from daily injections to long-acting formulations represents a transformative milestone in pediatric endocrinology. By leveraging diverse PEGylation strategies—ranging from symmetrical branched conjugates to innovative prodrug platforms—manufacturers have successfully optimized elimination half-lives and significantly improved patient adherence.

Hutaneg Pharma is a leading provider of high-purity PEG linkers, specifically engineered to meet the rigorous demands of complex drug conjugation and biopharmaceutical development. By offering a comprehensive portfolio of high-purity polymers and customized linker solutions, Hutaneg Pharma empowers researchers and manufacturers to develop the next generation of stable, predictable, and efficacious long-acting therapies.

References:
Liang, Y., Wei, H., Yang, F., Zhang, H., Chen, L., Yao, H., Luo, X., Cheng, X., Yang, Y., Lian, Q., Du, H., Li, T., Li, P., Zhang, G., Song, F., Liang, L., Liu, D., Zhu, S., Gong, H., . . .  Luo, X. (2024). A Novel Y-Shaped Pegylated Recombinant Human Growth Hormone for Children With Growth Hormone Deficiency. The Journal of Clinical Endocrinology and M