Evolution and Future of Growth Plate Therapeutics

“… 1 There are several phases in chondrocyte development during longitudinal growth: the resting, proliferative, prehypertrophic, hypertrophic, and terminal phases. 2 …”

Section: Introductionmentioning

confidence: 99%

“…1 There are several phases in chondrocyte development during longitudinal growth: the resting, proliferative, prehypertrophic, hypertrophic, and terminal phases. 2 Growth hormone (GH) is critical for promoting height. GH binds to growth hormone receptors (GHRs), activates Janus kinase 2…”

mentioning

confidence: 99%

Downregulation of ACAN is Associated with the Growth hormone pathway and Induces short stature

Wang

Shibata

et al. 2023

Clinical Laboratory Analysis

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Background ACAN heterozygous mutations can cause short stature in patients with or without advanced bone age and have recently attracted researchers' attention. Growth hormone can be used to treat short stature induced by ACAN mutations; however, few studies have focused on the underlying mechanism of this treatment. Methods Four patients with new mutations were reported based on clinical data and genetic tests. We investigated the expression and Gene Ontology biological process enrichment of ACAN and GH pathways based on GTEx databases through bioinformatics analyses. The effect of ACAN on the growth hormone response evaluated in ATDC5 cells with a growth hormone stimulation test. Results Four mutations were reported in this study: c.619C > A, c.1967A > G, c.1888G > A, and c.1308_1309del. All patients' heights were under −2.5 SD, with one had advanced bone age, and two had GH deficiency. Two individuals received growth hormone therapy acquired variable levels of height SD score improvement. ACAN and the GH pathway were strongly associated; ACAN does not affect GHR but regulates the response to GH. Downregulating ACAN inhibited ATDC5 cell proliferation induced by GH. Conclusion ACAN is associated with the GH pathway, revealing the potential mechanism underlying GH‐targeted treatment for ACAN mutation‐induced short stature. GH‐promoting therapies may increase patients' heights.

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“… 41 Therefore, theoretical concerns about transient elevations of GH and IGF-I that occur with each LAGH dose may lead providers to hesitate when considering LAGH therapy in cancer survivors with PGHD. 42 As more safety and efficacy data for LAGH emerges and as experience with lonapegsomatropin and other LAGH products grows, it is possible that LAGH may potentially replace DGH in the treatment of PGHD.…”

Section: Introductionmentioning

confidence: 99%

Spotlight on Lonapegsomatropin Once-Weekly Injection and Its Potential in the Treatment of Growth Hormone Deficiency in Pediatric Patients

Miller¹,

Yuen²

2022

DDDT

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Lonapegsomatropin, a long-acting GH therapy (LAGH), was approved by the United States Food and Drug Administration in August 2021 for the treatment of pediatric growth hormone deficiency (GHD). Lonapegsomatropin is a prodrug consisting of unmodified GH transiently conjugated to methoxypolyethylene glycol which enables time-release of GH with a half-life of ~25 hours allowing for onceweekly administration. Clinical trials of lonapegsomatropin have demonstrated positive efficacy results in children (phase 2 and 3) and adults (phase 2) with GHD. The phase 3 trial in children with GHD established non-inferiority and statistical superiority of height velocity with lonapegsomatropin (11.2 cm/yr) compared to daily GH (10.3 cm/yr), with no concerning side effects with lonapegsomatropin. Similar growth responses have been reported in other LAGH products in phase 2 (somapacitan) and phase 3 (somatrogon) trials. Lonapegsomatropin is distributed in temperature-stable, prefilled cartridges at 9 different doses that can be prescribed based upon specific weight brackets designed to deliver approximately 0.24 mg/kg/wk. An electronic delivery device is required to combine the powdered medication with the diluent and deliver the medication subcutaneously through a small gauge needle to the recipient. The pharmacodynamic data from the clinical trials of lonapegsomatropin has been used to develop models to estimate an average IGF-1 value drawn at any time during the weekly injection interval. This average IGF-1 value may be used to for safety monitoring and/or to guide dose adjustment. New LAGH products, including lonapegsomatropin, may potentially improve patient adherence, quality of life and clinical outcomes, particularly in patients with poor adherence to daily GH injections in the future. With the availability of new LAGH products, clinicians will need to identify the best candidates for LAGH therapy and understand how to monitor and adjust therapy. Long-term surveillance studies are needed to demonstrate adherence, efficacy, cost-effectiveness and safety of LAGH preparations.

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Evolution and Future of Growth Plate Therapeutics

Cited by 16 publications

References 101 publications

Role of hormones in bone remodeling in the craniofacial complex: A review

Role of hormones in bone remodeling in the craniofacial complex: A review

Downregulation of ACAN is Associated with the Growth hormone pathway and Induces short stature

Spotlight on Lonapegsomatropin Once-Weekly Injection and Its Potential in the Treatment of Growth Hormone Deficiency in Pediatric Patients

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