Growth hormone deficiency (GHD) is a condition caused by insufficient amounts of growth hormone in the body. Children with GHD have abnormally short stature with normal body proportions. Currently, growth hormone supplementation is recognized as one of the most effective treatments for children with GHD.

Human growth hormone (HGH) is a peptide hormone secreted by the anterior pituitary gland, consisting of 191 amino acids. It promotes growth in bones, organs, and the entire body, aids in protein synthesis, and influences fat and mineral metabolism, playing a key role in human growth and development. Typically, HGH is produced using recombinant Escherichia coli secretion technology, ensuring the amino acid content, sequence, and protein structure are identical to human growth hormone.

Currently, the most commonly used clinical treatment involves daily subcutaneous injections, which can be a significant burden on a child's daily life. Additionally, long-term use of daily injections often leads to poor treatment adherence, resulting in missed doses or insufficient medication, which may affect the treatment effectiveness. Therefore, there is an urgent clinical need to reduce the frequency of injections. Developing long-acting growth hormone (LAGH) formulations to improve adherence and treatment outcomes has become a primary focus.

Approved Long-acting Growth Hormone

Scientists began pursuing the development of long-acting growth hormone (LAGH) formulations as early as the 1980s. Companies such as Genentech (now part of Roche), Pfizer, and Novo Nordisk were early leaders in this field. However, due to substantial technical barriers, progress in LAGH development faced significant challenges.

In the early stages, several drugs in development were discontinued due to safety concerns or poor efficacy, including PEGylated growth hormones from Novo Nordisk and Pfizer, as well as growth hormone fusion proteins from Teva and Versartis. In 1999, Genentech achieved a milestone with FDA approval of Nutropin Depot, the world's first LAGH formulation using depot technology. However, this product was withdrawn five years later due to issues with large injection volumes and frequent reactions at the injection site.

Since then, various approaches have been explored for LAGH development, including depot formulations, PEGylated molecules, prodrug compounds, non-covalent binding to albumin, and growth hormone fusion proteins. Today, multiple LAGH formulations are under development, with four therapies already approved for the treatment of pediatric growth hormone deficiency (PGHD): Novo Nordisk's Sogroya, Ascendis' Skytrofa, Pfizer’s Ngenla, and GenSci ’s Jintrolong. Several others are currently in various stages of clinical trials.

Table. Approved long-acting growth Hormone

Long Acting Strategies

Currently, all four LAGH products are administered as once-weekly subcutaneous injections. By analyzing the basic principles behind their long-acting technology, it's clear that each of them modifies or protects the growth hormone molecule in different ways. These modifications increase the molecule's size, helping it avoid rapid metabolism and clearance by the body, thereby extending its duration of action.

Permanent Modification Technology

Except for lonapegsomatropin, the other long-acting growth hormone therapies use permanent modification techniques. This involves permanently attaching another molecule, such as polyethylene glycol (PEG), fusion proteins, or fatty acid side chains (which bind to large molecules like albumin once inside the body), to the growth hormone, creating recombinant human growth hormone analogs. These modifications increase the molecular weight of the drug, slowing its metabolic clearance.

However, this permanent modification changes the natural structure of the growth hormone, thereby affecting its pharmacological properties and biological activity. For instance, permanently modified growth hormone molecules exhibit a significantly reduced affinity for growth hormone receptors, requiring higher blood concentrations to achieve therapeutic effects. Moreover, growth hormone not only acts on receptors in the liver and other tissues but also on the growth plates of bones. Molecules that are too large may struggle to penetrate growth plates, which receive limited blood flow, thereby diminishing their ability to promote bone growth.

Transient Conjugation (TransCon) Technology

Lonapegsomatropin (Skytrofa) utilizes the TransCon platform, a transient conjugation technology, to achieve its long-acting effects. In this approach, the growth hormone molecule is temporarily linked to an inert carrier molecule, such as mPEG, forming an inactive prodrug. This design shields and protects the growth hormone molecule from rapid degradation and receptor-mediated clearance after injection, thus extending its half-life in the body.

Unlike permanent modification, the bond between the growth hormone and its inert carrier in lonapegsomatropin is temporary. After injection, the linkage automatically breaks down under physiological pH and temperature, gradually releasing "natural" growth hormone identical to endogenous human growth hormone. This enables the drug to maintain the same tissue distribution and physiological activity as the body's own hormone, including direct action on the growth plates to stimulate bone growth.

Ascendis, the company behind lonapegsomatropin, is an innovative biopharmaceutical company based in Denmark. Its TransCon platform is also applied to other drugs requiring extended half-lives. These include Yorvipath (palopegteriparatide), recently approved in the EU, UK, and US for hormone replacement therapy in hypoparathyroidism, and navepegritide, which is currently in Phase 3 clinical trials for the treatment of achondroplasia.

Conclusion

Product innovation is driving significant transformation in the growth hormone industry. Long-acting growth hormone formulations, with their ability to greatly enhance treatment adherence, are steadily gaining market traction and are poised to become the industry standard. Looking forward, there is strong anticipation that a breakthrough product in the long-acting growth hormone space will emerge in the near future, setting new benchmarks for the market.

Huateng Pharma, as a leading PEG derivative supplier, can provide monodispersed, polydispersed and multi-arm PEGs from grams to 100 kilograms to meet your drug development needs. Contact us at sales@huatengusa.com for more details.

References:

[1] Grillo MS, Frank J, Saenger P. Long acting growth hormone (LAGH), an update. Front Pediatr. 2023 Sep 28;11:1254231. doi: 10.3389/fped.2023.1254231. PMID: 37842029; PMCID: PMC10569466.

[2] Gilfoyle, David et al. “A first-in-man phase 1 trial for long-acting TransCon Growth Hormone.” Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 39 (2017): 34-39 .