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

Figures & data

Table 1 Timeline of Events in the Development of Lonapegsomatropin

Year(s)	Event	Trial Number
2009–2010	Adult Phase I Trial –Healthy Volunteers	NCT01010425
2010–2011	Phase II Trial Adult GHD	NCT01247675
2013–2015	Phase II Trial Pediatric GHD	NCT01947907
2016–2019	Phase III Trial Pediatric GHD (heiGHt)	NCT02781727
2017–2019	Phase III Trial Pediatric GHD (fliGHt)	NCT03305016
2017-Ongoing	Phase III Extension Trial Pediatric GHD (enliGHten)	NCT03344458
2020-Ongoing	Phase III Trial Adult GHD (foresiGHt)	NCT04615273
2021 (August)	FDA Approval Pediatric GHD
2021-Ongoing	Phase III Extension Trial Adult GHD	NCT05171855

Note: Available at clinicaltrials.gov.

Abbreviations: GHD, growth hormone deficiency; NCT number, National Clinical Trial number; FDA, Food and Drug Administration.

Figure 1 Timeline of daily GH and long-acting GH product availability.

Notes: The timeline shows the year each GH product became available. *GH-gelatin was never approved for use.

Abbreviations: Pit-hGH, pituitary human growth hormone; GH, growth hormone; rhGH, recombinant human growth hormone; PGHD, pediatric growth hormone deficiency; AGHD, adult growth hormone deficiency; USA, United States of America; LAGH, long-acting growth hormone; EU, European Union.

Figure 2 Schematic overview of lonapegsomatropin.²⁴

Notes: Lonapegsomatropin is a sustained-release inactive prodrug consisting of unmodified GH transiently bound to an inert carrier via a proprietary linker. The linker undergoes predictable autohydrolysis under physiologic pH and temperature, releasing fully active GH at the GH receptor. The inert carrier is primarily cleared by renal excretion. Adapted from Thornton PS, Maniatis AK, Aghajanova E, et al. Weekly lonapegsomatropin in treatment-naive children with growth hormone deficiency: the Phase 3 heiGHt trial. J Clin Endocrinol Metab. 2021;106(11):3184–3195. Copyright © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/).²⁴

Abbreviations: GH, growth hormone; hGH, human growth hormone; TransCon, transiently conjugated.

Table 2 Comparison of Growth Responses Between Long-Acting and Daily Growth Hormones in Pediatric Growth Hormone Deficiency.^16,24,29

	lonapegsomatropin (Phase 3)	Somatrogon (Phase 3)	Somapacitan (Phase 2)
Mechanism	Reversible PEGylation	Fusion Protein with hCG CTP (x3)	Acylation increases binding to Albumin
Molecular weight of the active agent (kDa)	22	41	23.3
Dose (mg/kg/wk)	0.24	0.66	0.16
Height velocity LAGH (cm/yr)	11.2	10.1	11.5
Height velocity DGH (cm/yr)	10.3	9.8	10.5
Estimated average IGF-1 SDS on LAGH	+0.72	Data not available	+0.31

Notes: Height velocity data from Phase 2 (Somapacitan) and Phase 3 (Lonapegsomatropin and Somatrogon). The DGH dose was 0.034 mg/kg/day (0.24 mg/kg/wk) in each study. Estimated average IGF-1 SDS was based upon LAGH product specific pharmacokinetic modeling.

Abbreviations: cm, centimeter; CTP, C-terminal peptide; DGH, daily growth hormone; hCG, human chorionic gonadotropin; IGF-I, insulin-like growth factor I; kDa, kilodalton; kg, kilogram; mg, milligram; SDS, standard deviation score; wk, week; yr, year.

Table 3 The Predicted Difference Between Observed IGF-I SDS and Average IGF-I SDS and Predicted Ratio Between IGF-I and Average IGF-I Concentrations by time²⁵

Day	Mean Difference from Average IGF-I SDS	IGF-I Concentration Ratio
0.0	−1.22	0.62
0.5	−0.12	0.96
1.0	0.39	1.14
1.5	0.60	1.22
2.0	0.67	1.25
2.5	0.68	1.25
3.0	0.62	1.23
3.5	0.46	1.17
4.0	0.21	1.07
4.5	−0.09	0.97
5.0	−0.39	0.87
5.5	−0.64	0.79
6.0	−0.85	0.73
6.5	−1.07	0.67
7.0	−1.22	0.62

Notes: These tables may be used to estimate the average IGF-I value at steady state. It is necessary to know the day/time of injection to the nearest half day and the day/time of venipuncture for IGF-I measurement to determine the number of days since the injection. The estimated average IGF-I SDS can be determined by subtracting the value listed for the number of days since injection the sample was drawn from the measured IGF-I SDS (Average IGF-I SDS=IGF-I SDS on Day X – difference between measured IGF-I SDS on Day X and average IGF-I SDS on Day X). Similarly, the estimated average IGF-I concentration can be determined by dividing the measured IGF-I concentration value by the ratio listed for the number of days since injection the sample was drawn (Average IGF-1 concentration=IGF-1 concentration on Day X ÷ IGF-I ratio on Day X). Adapted from Lin Z, Shu AD, Bach M, Miller BS, Rogol AD, Average IGF-1. Prediction for once-weekly lonapegsomatropin in children with growth hormone deficiency. J Endocr Soc. 2022;6(1):bvab168. © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/).²⁵

Abbreviations: IGF-I, insulin-like growth factor I; SDS, standard deviation score.

Table 4 Recommended Dosing for Patients Prescribed Doses of 0.24 mg/kg/Week Based Upon Available Cartridge size³⁹

Weight (kg)	Dose (mg)
11.5–13.9	3
14–16.4	3.6
16.5–19.9	4.3
20–23.9	5.2
24–28.9	6.3
29–34.9	7.6
35–41.9	9.1
42–50.9	11
51–60.4	13.3
60.5–69.9	15.2 (using 2 cartridges of 7.6 mg)
70–84.9	18.2 (using 2 cartridges of 9.1 mg)
85–100	22 (using 2 cartridges of 11 mg)

Note: Reproduced with permission from Ascendis. SKYTROFA™ (lonapegsomatropin-tcgd) for injection, for subcutaneous use; 2021. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761177lbl.pdf. © 2022 Ascendis Pharma. All rights reserved. SKYTROFA™, Ascendis^®, TransCon^®, the Ascendis Pharma logo and the company logo are trademarks owned by the Ascendis Pharma Group.³⁹

Figure 3 Skytrofa electronic delivery device and its features.³⁹

Note: Reproduced with permission from Ascendis. SKYTROFA™ (lonapegsomatropin-tcgd) for injection, for subcutaneous use; 2021. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761177lbl.pdf. © 2022 Ascendis Pharma. All rights reserved. SKYTROFA™, Ascendis^®, TransCon^®, the Ascendis Pharma logo and the company logo are trademarks owned by the Ascendis Pharma Group.³⁹

Abbreviations: GH, growth hormone; mm, millimeter; SC, subcutaneous.

Thornton PS, Maniatis AK, Aghajanova E, et al. Weekly lonapegsomatropin in treatment-naive children with growth hormone deficiency: the Phase 3 heiGHt trial. J Clin Endocrinol Metab. 2021;106(11):3184–3195. doi:10.1210/clinem/dgab529

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Pfizer. OPKO and pfizer announce positive Phase 3 top-line results for somatrogon, an investigational long-acting human growth hormone to treat children with growth hormone deficiency; 2019. Available from: https://www.pfizer.com/news/press-release/press-release-detail/opko_and_pfizer_announce_positive_phase_3_top_line_results_for_somatrogon_an_investigational_long_acting_human_growth_hormone_to_treat_children_with_growth_hormone_deficiency. Accessed February 24, 2022.

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Savendahl L, Battelino T, Brod M, et al. Once-weekly somapacitan vs daily GH in children with GH deficiency: results from a randomized Phase 2 trial. J Clin Endocrinol Metab. 2020;105(4):01. doi:10.1210/clinem/dgz310

 PubMed Web of Science ®Google Scholar

Lin Z, Shu AD, Bach M, Miller BS, Rogol AD, Average IGF-1. Prediction for once-weekly lonapegsomatropin in children with growth hormone deficiency. J Endocr Soc. 2022;6(1):bvab168. doi:10.1210/jendso/bvab168

 PubMed Web of Science ®Google Scholar

Ascendis. SKYTROFA™ (lonapegsomatropin-tcgd) for injection, for subcutaneous use; 2021. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761177lbl.pdf. Accessed February 12, 2022.

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