Developments in the Management of Growth Hormone Deficiency: Clinical Utility of Somapacitan

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Table 1 Summary and Comparison of Approved Long-Acting Growth Hormones, Including Somapacitan

	Novo Nordisk	Ascendis	Pfizer/OPKO Health
	Somapacitan	Lonapegsomatropin, TransCon hGH	Somatrogon
Molecular weight (g/mol)	23,305.10^a	22,000^b	41,000^c
Protraction technique	Reversible albumin binding^d	Transient PEGylation^e	CTP fusion^c
Half-life, hours
Adults	48–72^d	18–43.4^f	20.8–23.6^c
Children	34^d	30.7^f	18.3–36.1^c
Elimination technique	Metabolized by proteolytic degradation and cleavage of the linker sequence between the peptide and albumin binder^d	Catabolized in the liver and kidney to its constitutive amino acids^g	Primarily degraded by proteolytic catabolism^c
Dosing interval	Once weekly^d	Once weekly^e	Once weekly^c
Cmax	0.02 mg/kg: 14.4 ng/mL 0.04 mg/kg: 19.8 ng/mL 0.08 mg/kg: 64.2 ng/mL 0.12 mg/kg: 142.5 ng/mL^h	0.24 mg/kg: 15.2 ng/mL^g	0.66 mg/kg: 690 ng/mL^c
Formulation	Liquid, subcutaneous^d	Freeze dried in dual chamber cartridge, subcutaneous^f	Liquid, subcutaneous^c
Development	AGHD: approved^d CGHD: approved^d	AGHD: Phase 3 initiated^i CGHD: approved*^g	AGHD: failed primary endpoint at phase 3^j CGHD: approved**

Notes: *Approved in the USA and EU; **Approved in the EU and a complete response letter issued in the USA. ^aSogroya^® Novo-PI.2023. Available at: https://www.novo-pi.com/sogroya.pdf;^{14 b}Miller BS, Yuen KCJ. Drug Des Devel Ther 2022;16:2055–2066;^{15 c}Assessment report: Ngenla^®.EMA, 2021. Available at: https://www.ema.europa.eu/en/documents/assessment-report/ngenla-epar-public-assessment-report_en.pdf;^{16 d}Sogroya^® SmPC. EMA, 2023. Available at: https://www.ema.europa.eu/en/documents/product-information/sogroya-epar-product-information_en.pdf;^{17 e}Lonapegsomatropin SmPC. EMA, 2022. Available at: https://www.ema.europa.eu/en/documents/product-information/skytrofa-previously-lonapegsomatropin-ascendis-pharma-epar-product-information_en.pdf;^{18 f}Lonapegsomatropin PI. FDA 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761177s001lbl.pdf;^{19 g}Assessment report: Lonapegsomatropin^® EMA, 2021. Available at: https://www.ema.europa.eu/en/documents/assessment-report/lonapegsomatropin-ascendis-pharma-epar-public-assessment-report_en.pdf;^{20 h}Højby Rasmussen et al J Clin Endocrinol Metab 2016;101(3):988–998;^{21 i}ClinialTrials.gov: NCT05171855. Available at: https://classic.clinicaltrials.gov/ct2/show/NCT05171855;^{22 j}ClinicalTrials.gov: NCT01909479. Available at: https://classic.clinicaltrials.gov/ct2/show/NCT01909479.²³

Abbreviations: AGHD, adult growth hormone deficiency; CGHD, childhood growth hormone deficiency; C_max, maximum serum concentration; CTP, carboxyl terminal peptide; hGH, human growth hormone; PEG, polyethylene glycol.

Figure 1 Molecular structure of somapacitan.

Notes: Figure adapted from Petersen M, Gandhi PS, Buchardt J et al. Tissue distribution and receptor activation by somapacitan, a long acting growth hormone derivative. Int J Mol Sci. 2020;21(4):1181. Creative Attribution 4.0 International (CC BY 4.0).²⁹

Table 2 Summary of the Efficacy Endpoints of Long-Acting Growth Hormones, Including Somapacitan, Investigated in Treatment-Naive Pediatric Populations Over a 12-Month Period

Trial	Number of Participants (Age Range, Years)	Mean AHV of LAGH (cm/year)	Mean AHV of Daily GH (cm/year)	ETD in AHV at Week 52 Between LAGH and Daily GH Comparator (95% CI)	Change in HSDS from Baseline*	Change in IGF-I SDS	Mean IGF-I SDS at Week 52
REAL 4^a Somapacitan	n = 200 Age range: girls 2.5–10 and boys 2.5–11	11.2	11.7	−0.5 (−1.1 to 0.2)	1.25	2.36	0.28
NCT02968004^b Somatrogon	n = 228 Age range: girls 3–10 and boys 3–11	10.10	9.78	0.33 (−0.24 to 0.89)
NCT03874013 (Japan)^c Somatrogon	n = 44 Age range: girls 3 to <10 and boys 3 to <11	9.65	7.87	1.79 (0.97 to 2.61)	0.94
HeiGHt^d Lonapegsomatropin	n = 161 Age range: girls 3–11 years and boys 3–12 years	11.2	10.3	0.9 (0.2 to 1.5)	1.10		0.72

Notes: *Change in HSDS from baseline was for the following time period: REAL 4, 52 weeks; NCT03874013 (Japan), 12 months; HeiGHt, 52 weeks. The treatment product and the dose for each trial were as follows: REAL 4, somapacitan 0.16 mg/kg/week; NCT02968004 and NCT03874013 (Japan), somatrogon 0.66 mg/kg/week; HeiGHt, lonapegsomatropin 0.24 mg/kg/week. ^aMiller et al J Clin Endocrinol Metab 2022;107(12):3378–3388;^{39 b}Deal et al J Clin Endocrinol Metab. 2022;107(7): e2717-e2728;^{43 c}Horikawa et al Horm Res Paediatr. 2022;95(3):275–285;^{44 d}Thornton et al J Clin Endocrinol Metab 2021;106(11):3184–3195.⁴⁵

Abbreviations: AHV, annualized height velocity; CI, confidence intervals; ETD, estimated treatment difference; GH, growth hormone; HSDS, height standard deviation score; IGF-I, insulin-like growth factor-I; LAGH, long-acting growth hormone; n, number of participants; SDS, standard deviation score.

Figure 2 Treatment burden scores for participants with CGHD and their parents/guardians in the REAL 3 trial. (A) Growth Hormone Deficiency–Child Treatment Burden (GHD-CTB) and (B) Growth Hormone Deficiency–Parent Treatment Burden (GHD-PTB) mean (SD) scores at years 2, 3, and 4.

Note: ^aThe increase in GHD-CTB and GHD-PTB mean (SD) scores in the daily GH/somapacitan group between years 2 and 3 can largely be attributed to two patients, who may have experienced greater treatment fatigue compared with the rest of the cohort. Total scores range from 0 to 100. Data from Sävendahl et al.³⁸

Abbreviations: CGHD, childhood growth hormone deficiency; GH, growth hormone; SD, standard deviation.

Figure 3 Somapacitan administration pens.

Table 3 Summary of Main Recommendations for Clinicians About Adults and Children with GHD Receiving Somapacitan

Recommendation Type	AGHD	CGHD
Dosing	Initiate somapacitan at a dose of 1.5 mg once weekly for treatment-naive participants and participants switching from daily GH Initiate higher starting doses of 2 mg once weekly for younger participants and women on oral estrogen Initiate lower starting doses of 1 mg once weekly for participants aged ≥65 years Increase the weekly dosage every 2–4 weeks by approximately 0.5 mg to 1.5 mg until the desired response is achieved Titrate the dose based on clinical response and serum IGF-I levels Initiating a lower dose and using smaller dose increments for individuals with moderate hepatic impairment Decrease the dosage as necessary on the basis of adverse reactions and/or serum IGF-I levels above the age and sex-specific normal range The maximum recommended dosage is 8 mg once weekly Administer a missed dose as soon as possible and no later than 3 days If more than 3 days have passed since the missed dose, skip the dose and administer the next dose on the regular dosing day	Initiate somapacitan at a dose of 0.16 mg/kg body weight, individualizing the dose thereafter based on growth response Administer a missed dose as soon as possible and no later than 3 days If more than 3 days have passed since the missed dose, skip the dose and administer the next dose on the regular dosing day Change the dosage in 10–20% increments If possible, adjust the dose after 2 elevated IGF-I measures
Monitoring	Draw IGF-I samples 3–4 days after the prior dose	Draw IGF-I samples 3–4 days after the prior dose
Transition		Participants who were treated with somapacitan for CGHD in whom the epiphyses are closed should be reevaluated before continuing For participants switching from daily GH to somapacitan, the final daily dose should be administered the day before switching, or at least 8 hours before the administration of the first somapacitan dose Carefully monitor height, weight, growth velocity, bone age, and IGF-I when transitioning a patient from daily GH to somapacitan

Abbreviations: AGHD, adult growth hormone deficiency; CGHD, childhood growth hormone deficiency; GH, growth hormone; GHD, growth hormone deficiency; IGF-I, insulin growth factor-1.

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