Identification

Summary

Lonapegsomatropin is a human growth hormone indicated in the treatment of growth failure due to inadequate endogenous growth hormone secretion.

Brand Names
Skytrofa
Generic Name
Lonapegsomatropin
DrugBank Accession Number
DB16220
Background

Lonapegsomatropin, also known as TransCon hGH or ACP 001, is a methoxypegylated prodrug of human growth hormone (somatropin) indicated for the treatment of children 1 year and older, weighing at least 11.5 kg, with growth failure due to insufficient growth hormone secretion.1,3,4 Unlike somatropin, which requires daily dosing, lonapegsomatropin can be administered as a single weekly dose.3,5

Lonapegsomatropin was granted FDA approval on 25 August 2021.3 It was later approved by the European Commission on 13 January 2022.7

Type
Biotech
Groups
Approved, Investigational
Synonyms
  • Lonapegsomatropin
  • lonapegsomatropin-tcgd
  • RhGH-PEG
  • Transconpeg hGH
  • Transconpeg-hGH
External IDs
  • ACP-011

Pharmacology

Indication

In the US, lonepegsomatropin is indicated in the treatment of growth failure due to inadequate growth hormone secretion in patients one year and older who weigh at least 11.5 kg.3 In Europe, lonepegsomatropin is indicated to treat growth failure in children and adolescents aged from three years up to 18 years due to insufficient endogenous growth hormone secretion or growth hormone deficiency.8

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Lonapegsomatropin-tcgd is a growth hormone prodrug indicated in the treatment of growth failure due to inadequate growth hormone secretion in patients 1 year and older who weigh at least 11.5 kg.3 It has a long duration of action as it is given weekly.3 Patients and carers should be counselled regarding the risks of severe hypersensitivity, neoplasms, glucose intolerance, intracranial hypertension, fluid retention, hypoadrenalism, hypothyroidism, slipped capital femoral epiphysis, progression of preexisting scoliosis, and pancreatitis.3

Mechanism of action

Lonapegsomatropin-tcgd undergoes autocleavage to release active somatropin from the methoxypolyethylene glycol carrier.3 Somatropin binds to the growth hormone receptor leading to direct effects and insulin-like growth factor-1 mediated indirect effects.3 Somatropin has effects on the epiphyses of long bones, leading to growth in pediatric patients.3 Somatropin also stimulates chondrocyte differentiation and proliferation, release of glucose from the liver, protein synthesis, and lipolysis.3

Somatotropin mediates its effects both directly by somatotropin and indirectly by insulin-like growth factor-1 (IGF-1), which is upregulated by growth hormone. It binds to the human growth hormone receptor (GHR), which is a dimeric receptor expressed in target cells in the liver and cartilage.5 Upon binding of growth hormone, GHR dimerizes and interacts with Janus kinase 2 (JAK2), subsequently leading to tyrosine phosphorylation of JAK2 and the GH receptor. The signal transducer activator of transcription (STAT) pathway is initiated, where transcription factors such as STAT1, STAT3, and STAT5 are translocated into the nucleus to stimulate target gene transcription.6

At the epiphysis or growth plate, growth hormone increases linear growth by promoting differentiation of prechondrocytes and expansion of osteoblasts. Growth hormone binding to its receptor in the liver and cartilage promotes the production of IGF-1, which acts on type 1 IGF receptors to also stimulate linear growth. In the liver, activated growth hormone receptor signalling leads to increased production of IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS), which are proteins that bind to IGF-1 in a ternary complex to increase its half-life.2

TargetActionsOrganism
AGrowth hormone receptor
ligand
Humans
AProlactin receptor
ligand
Humans
Absorption

After subcutaneous lonapegsomatropin-tcgd administration, the drug undergoes autocleavage, releasing active somatropin from the methoxypolyethylene glycol carrier.3 0.24 mg/kg/week dosing in pediatric patients leads to a somatropin Cmax of 15.2 ng/mL, with a median Tmax of 12 hours, and a mean AUC of 500 h*ng/mL.3

Methoxypolyethylene glycol reaches a Cmax of 13.1 µg/mL, with a meadian Tmax of 36 hours.3

Human growth hormone (somatropin) concentrations reach a mean steady Cmax of 1230 ng/mL, with a Tmax of 25 hours.3

Volume of distribution

Lonapegsomatropin-tcgd dosing of 0.24 mg/kg/week leads to a mean steady state apparent volume of distribution of 0.13 L/kg.3

Protein binding

Not Available

Metabolism

Lonapegsomatropin-tcgd is a prodrug that undergoes autocleavage, releasing the active somatropin from the methoxypolyethelene glycol carrier.3 The methoxypolyethelene glycol carrier is cleared by the kidneys, while somatropin is metabolized by non-specific protein catabolic pathways in the liver and kidneys to smaller oligopeptides and individual amino acids.3

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Route of elimination

The methoxypolyethelene glycol carrier is cleared by the kidneys, while the active somatropin undergoes catabolic processes in the kidneys and liver.3 However, the exact proportions of lonapegsomatropin recovered in the urine and feces has not been reported.

Half-life

The half life of lonapegsomatropin-tcgd is 30.7 ± 12.7 hours, while the half life of released somatropin was approximately 25 hours.3

Clearance

In pediatric patients, the apparent clearance of lonapegsomatropin-tcgd is 3.2 mL/h/kg.3

Adverse Effects
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Toxicity

Patients experiencing an acute overdose may present with fluid retention and hypoglycemia followed by hyperglycemia.3 Chronic overdosage may present with signs of gigantism.3 Treat patients with symptomatic and supportive measures.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Lonapegsomatropin.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Lonapegsomatropin.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Lonapegsomatropin.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Lonapegsomatropin.
AcyclovirThe metabolism of Acyclovir can be increased when combined with Lonapegsomatropin.
AgomelatineThe metabolism of Agomelatine can be increased when combined with Lonapegsomatropin.
AlbendazoleThe metabolism of Albendazole can be increased when combined with Lonapegsomatropin.
AlbiglutideThe therapeutic efficacy of Albiglutide can be decreased when used in combination with Lonapegsomatropin.
AlogliptinThe therapeutic efficacy of Alogliptin can be decreased when used in combination with Lonapegsomatropin.
AlosetronThe metabolism of Alosetron can be increased when combined with Lonapegsomatropin.
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Food Interactions
No interactions found.

Products

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Active Moieties
NameKindUNIICASInChI Key
SomatotropinprodrugNQX9KB6PCL12629-01-5Not applicable
International/Other Brands
Skytrofa (Ascendis Pharma A/S)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Lonapegsomatropin Ascendis PharmaInjection, powder, for solution3.6 mgSubcutaneousAscendis Pharma Endocrinology Division A/s2022-05-04Not applicableEU flag
Lonapegsomatropin Ascendis PharmaInjection, powder, for solution9.1 mgSubcutaneousAscendis Pharma Endocrinology Division A/s2022-05-04Not applicableEU flag
Lonapegsomatropin Ascendis PharmaInjection, powder, for solution5.2 mgSubcutaneousAscendis Pharma Endocrinology Division A/s2022-05-04Not applicableEU flag
Lonapegsomatropin Ascendis PharmaInjection, powder, for solution3 mgSubcutaneousAscendis Pharma Endocrinology Division A/s2022-05-04Not applicableEU flag
Lonapegsomatropin Ascendis PharmaInjection, powder, for solution13.3 mgSubcutaneousAscendis Pharma Endocrinology Division A/s2022-05-04Not applicableEU flag
Lonapegsomatropin Ascendis PharmaInjection, powder, for solution7.6 mgSubcutaneousAscendis Pharma Endocrinology Division A/s2022-05-04Not applicableEU flag
Lonapegsomatropin Ascendis PharmaInjection, powder, for solution4.3 mgSubcutaneousAscendis Pharma Endocrinology Division A/s2022-05-04Not applicableEU flag
Lonapegsomatropin Ascendis PharmaInjection, powder, for solution11 mgSubcutaneousAscendis Pharma Endocrinology Division A/s2022-05-04Not applicableEU flag
Lonapegsomatropin Ascendis PharmaInjection, powder, for solution6.3 mgSubcutaneousAscendis Pharma Endocrinology Division A/s2022-05-04Not applicableEU flag
SkytrofaInjection, powder, lyophilized, for solution11 mg/1SubcutaneousAscendis Pharma Endocrinology, Inc.2021-08-25Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans

Chemical Identifiers

UNII
OP35X9610Y
CAS number
1934255-39-6

References

General References
  1. Thornton PS, Maniatis AK, Aghajanova E, Chertok E, Vlachopapadopoulou E, Lin Z, Song W, Christoffersen ED, Breinholt VM, Kovalenko T, Giorgadze E, Korpal-Szczyrska M, Hofman PL, Karpf DB, Shu AD, Beckert M: Weekly Lonapegsomatropin in Treatment-Naive Children with Growth Hormone Deficiency: The Phase 3 heiGHt Trial. J Clin Endocrinol Metab. 2021 Jul 17. pii: 6323258. doi: 10.1210/clinem/dgab529. [Article]
  2. Reh CS, Geffner ME: Somatotropin in the treatment of growth hormone deficiency and Turner syndrome in pediatric patients: a review. Clin Pharmacol. 2010;2:111-22. doi: 10.2147/CPAA.S6525. Epub 2010 Jun 1. [Article]
  3. FDA Approved Drug Products: Skytrofa (Lonapegsomatropin-tcgd) Subcutaneous Injection [Link]
  4. Clinical Trials: NCT02781727 [Link]
  5. FDA Approved Drug Products: Norditropin (somatropin) injection, for subcutaneous use [Link]
  6. StatPearls: Physiology, Growth Hormone [Link]
  7. BioSpace News: Ascendis Pharma A/S Receives European Approval for TransCon™ hGH for Pediatric Growth Hormone DeficiencyTransCon hGH [Link]
  8. Summary of Product Characteristics: Lonapegsomatropin subcutaneous injection [Link]
RxNav
2569562
Wikipedia
Lonapegsomatropin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentAdult Onset Growth Hormone Deficiency / Endocrine System Diseases / Hormone Deficiency1
3RecruitingTreatmentEndocrine System Diseases / Hormone Deficiency / Human Growth Hormone Deficiency1
3RecruitingTreatmentEndocrine System Diseases / Hormones / Human Growth Hormone Deficiency / Pituitary Disease, Anterior / Pituitary Diseases1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionSubcutaneous11 mg
Injection, powder, for solutionSubcutaneous13.3 mg
Injection, powder, for solutionSubcutaneous3 mg
Injection, powder, for solutionSubcutaneous3.6 mg
Injection, powder, for solutionSubcutaneous4.3 mg
Injection, powder, for solutionSubcutaneous5.2 mg
Injection, powder, for solutionSubcutaneous6.3 mg
Injection, powder, for solutionSubcutaneous7.6 mg
Injection, powder, for solutionSubcutaneous9.1 mg
Injection, powder, lyophilized, for solutionSubcutaneous11 mg/1
Injection, powder, lyophilized, for solutionSubcutaneous13.3 mg/1
Injection, powder, lyophilized, for solutionSubcutaneous3 mg/1
Injection, powder, lyophilized, for solutionSubcutaneous3.6 mg/1
Injection, powder, lyophilized, for solutionSubcutaneous4.3 mg/1
Injection, powder, lyophilized, for solutionSubcutaneous5.2 mg/1
Injection, powder, lyophilized, for solutionSubcutaneous6.3 mg/1
Injection, powder, lyophilized, for solutionSubcutaneous7.6 mg/1
Injection, powder, lyophilized, for solutionSubcutaneous9.1 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Ligand
General Function
Protein kinase binding
Specific Function
Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway (By similarity).The soluble form (GHBP) acts as a rese...
Gene Name
GHR
Uniprot ID
P10912
Uniprot Name
Growth hormone receptor
Molecular Weight
71498.885 Da
References
  1. Walenkamp MJ, Wit JM: Genetic disorders in the growth hormone - insulin-like growth factor-I axis. Horm Res. 2006;66(5):221-30. [Article]
  2. Wu XY, Xu Z, Chen C, Liu FK, Li JS: [Correlation of growth hormone receptor expression to preoperative radiosensitivity of rectal cancer patients]. Ai Zheng. 2006 Sep;25(9):1162-7. [Article]
  3. Adriani M, Garbi C, Amodio G, Russo I, Giovannini M, Amorosi S, Matrecano E, Cosentini E, Candotti F, Pignata C: Functional interaction of common gamma-chain and growth hormone receptor signaling apparatus. J Immunol. 2006 Nov 15;177(10):6889-95. [Article]
  4. Choi JH, Kim HS, Kim SH, Yang YR, Bae YS, Chang JS, Kwon HM, Ryu SH, Suh PG: Phospholipase Cgamma1 negatively regulates growth hormone signalling by forming a ternary complex with Jak2 and protein tyrosine phosphatase-1B. Nat Cell Biol. 2006 Dec;8(12):1389-97. Epub 2006 Nov 26. [Article]
  5. Bernstein RM, Leigh SR, Donovan SM, Monaco MH: Hormones and body size evolution in papionin primates. Am J Phys Anthropol. 2007 Feb;132(2):247-60. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  7. Reh CS, Geffner ME: Somatotropin in the treatment of growth hormone deficiency and Turner syndrome in pediatric patients: a review. Clin Pharmacol. 2010;2:111-22. doi: 10.2147/CPAA.S6525. Epub 2010 Jun 1. [Article]
  8. FDA Approved Drug Products: Skytrofa (Lonapegsomatropin-tcgd) Subcutaneous Injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Ligand
General Function
Protein homodimerization activity
Specific Function
This is a receptor for the anterior pituitary hormone prolactin (PRL). Acts as a prosurvival factor for spermatozoa by inhibiting sperm capacitation through suppression of SRC kinase activation and...
Gene Name
PRLR
Uniprot ID
P16471
Uniprot Name
Prolactin receptor
Molecular Weight
69505.045 Da
References
  1. Keeler C, Jablonski EM, Albert YB, Taylor BD, Myszka DG, Clevenger CV, Hodsdon ME: The kinetics of binding human prolactin, but not growth hormone, to the prolactin receptor vary over a physiologic pH range. Biochemistry. 2007 Mar 6;46(9):2398-410. Epub 2007 Feb 6. [Article]
  2. Ahmed TA, Buzzelli MD, Lang CH, Capen JB, Shumate ML, Navaratnarajah M, Nagarajan M, Cooney RN: Interleukin-6 inhibits growth hormone-mediated gene expression in hepatocytes. Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1793-803. Epub 2007 Mar 29. [Article]
  3. Moderscheim TA, Gorba T, Pathipati P, Kokay IC, Grattan DR, Williams CE, Scheepens A: Prolactin is involved in glial responses following a focal injury to the juvenile rat brain. Neuroscience. 2007 Mar 30;145(3):963-73. Epub 2007 Feb 20. [Article]
  4. Cunningham BC, Bass S, Fuh G, Wells JA: Zinc mediation of the binding of human growth hormone to the human prolactin receptor. Science. 1990 Dec 21;250(4988):1709-12. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
11-beta-hydroxysteroid dehydrogenase [nad(p)] activity
Specific Function
Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Catalyzes reversibly the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. In intact cells, the rea...
Gene Name
HSD11B1
Uniprot ID
P28845
Uniprot Name
Corticosteroid 11-beta-dehydrogenase isozyme 1
Molecular Weight
32400.665 Da
References
  1. FDA Approved Drug Products: Skytrofa (Lonapegsomatropin-tcgd) Subcutaneous Injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Jurgens G, Lange KH, Reuther LO, Rasmussen BB, Brosen K, Christensen HR: Effect of growth hormone on hepatic cytochrome P450 activity in healthy elderly men. Clin Pharmacol Ther. 2002 Mar;71(3):162-8. doi: 10.1067/mcp.2002.121373. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Jurgens G, Lange KH, Reuther LO, Rasmussen BB, Brosen K, Christensen HR: Effect of growth hormone on hepatic cytochrome P450 activity in healthy elderly men. Clin Pharmacol Ther. 2002 Mar;71(3):162-8. doi: 10.1067/mcp.2002.121373. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Wu SJ, Robinson JR: Transport of human growth hormone across Caco-2 cells with novel delivery agents: evidence for P-glycoprotein involvement. J Control Release. 1999 Nov 1;62(1-2):171-7. doi: 10.1016/s0168-3659(99)00035-8. [Article]

Drug created at December 15, 2020 18:15 / Updated at February 10, 2022 08:54