>Somatrogon amino acid sequence
SSSSKAPPPSLPSPSRLPGPSDTPILPQFPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFE
EAYIPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQF
LRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHN
DDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVEGSCGFSSSSKAPPPSLPSPSRLPGPS
DTPILPQSSSSKAPPPSLPSPSRLPGPSDTPILPQ

Somatrogon

CAS: 1663481-09-1

Protein Chemical FormulaC₁₃₅₉H₂₁₂₅N₃₆₁O₄₂₀S₇

Protein Average Weight30465.1 Da (Aglycosylated)

NGENLA, JAPAN PMDA APPROVED 2022/1/20

ソマトロゴン;

• MOD-4023

Replenisher (somatotoropin)

• OriginatorModigene
• DeveloperOPKO Health; Pfizer
• ClassBiological proteins; Growth hormones; Hormonal replacements; Recombinant proteins
• Mechanism of ActionHuman growth hormone replacements
• Orphan Drug StatusYes – Somatotropin deficiency
• RegisteredSomatotropin deficiency

• 21 Jan 2022Pfizer and OPKO health receives complete response letter from the US FDA for somatrogon in Somatotropin deficiency (In children)
• 20 Jan 2022Registered for Somatotropin deficiency (In children) in Japan (SC)
• 01 Dec 2021CHMP issues a positive opinion and recommends approval of somatrogon for Somatotropin deficiency in the European Union

Somatrogon, sold under the brand name Ngenla, is a medication for the treatment of growth hormone deficiency.^[1][2] Somatrogon is a glycosylated protein constructed from human growth hormone and a small part of human chorionic gonadotropin which is appended to both the N-terminal and C-terminal.^[2]

Somatrogon is a long-acting recombinant human growth hormone used as the long-term treatment of pediatric patients who have growth failure due to growth hormone deficiency.

omatrogon is a long-acting recombinant human growth hormone. Growth hormone is a peptide hormone secreted by the pituitary gland that plays a crucial role in promoting longitudinal growth during childhood and adolescence and regulating metabolic function in adulthood.² Recombinant growth hormone therapy for growth hormone deficiency and other conditions has been available since 1985, with daily administration being the standard treatment for many years. More recently, longer-acting forms of growth hormone were developed to improve patient adherence and thus, improve the therapeutic efficacy of treatment.¹ Somatrogon was produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology. It is a chimeric product generated by fusing three copies of the C-terminal peptide (CTP), or 28 carboxy-terminal residues, from the beta chain of human chorionic gonadotropin (hCG) to the N-terminus and C-terminus of human growth hormone.^2,6 The glycosylation and the presence of CTPs in the protein sequence prolongs the half-life of somatrogon and allows its once-weekly dosing.⁶

In October 2021, Health Canada approved somatrogon under the market name NGENLA as the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone caused by growth hormone deficiency, marking Canada as the first country to approve this drug.⁴ It is available as a once-weekly subcutaneous injection.⁵

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About Somatrogon^©

Somatrogon^©, a long-acting human growth hormone (hGH) molecule, is a once-weekly injectable, created using recombinant technology, for the treatment of pediatric and adult growth hormone deficiency (GHD). The molecule consists of the natural peptide sequence of native growth hormone and the 28 amino acids of the C-Terminus Peptide (CTP) of the human chorionic gonadotropin hormone. This molecule, as compared to current GH replacement therapies, is intended to reduce the injection frequency from a daily to once a week in adults and children with GHD.

Clinical data
Trade names	Ngenla
Other names	MOD-4023
Pregnancy category	AU: B1[1]
Routes of administration	Subcutaneous injection
ATC code	H01AC08 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) [1]
Identifiers
CAS Number	1663481-09-1
DrugBank	DB14960
UNII	6D848RA61B

Somatrogon^© COMPETITIVE ADVANTAGES

In 2014, Pfizer and OPKO entered into a worldwide agreement for the development and commercialization of Somatrogon^©. Under the agreement, OPKO is responsible for conducting the clinical program and Pfizer is responsible for registering and commercializing the product.

• New molecular entity (NME) that maintains natural native sequence of growth hormone
• Once weekly injection vs. current products requiring daily injections
• Human growth hormone is used for:
  • Growth hormone deficient children and adults
  • SGA, PWS, ISS
• Final presentation:
  • Refrigerated, liquid, non-viscous formulation
  • Disposable easy to handle pen injection device with thin needle and small injection volume
• Orphan drug designation in the U.S. and the EU for children and adults

Somatrogon^© PROGRAM STATUS

Phase 3 Pediatric Somatrogon^©

• Phase 3 study in naive growth hormone deficiency pediatric population was completed.

The study was conducted in over 20 countries. This study enrolled and treated 224 pre-pubertal, treatment-naive children with growth hormone deficiency.

• OPKO and Pfizer Announce Positive Phase 3 Top-Line Results for Somatrogon^© during Oct 2019.
• Achieved Primary Endpoint
  • Somatrogon^© was proven non-inferior to daily Genotropin® (somatropin) with respect to height velocity after 12 months
  • Height velocity at 12 months of treatment was higher in the Somatrogon^© group (10.12 cm/year) than in the somatropin group (9.78 cm/year)
• Secondary Endpoints Achieved
  • Change in height standard deviation scores at six and 12 months were higher with Somatrogon^© in comparison to somatropin
  • At six months, change in height velocity was higher with Somatrogon^© in comparison to somatropin
  • Somatrogon^© was generally well tolerated in the study and comparable to that of somatropin dosed once-daily with respect to the types, numbers and severity of the adverse events observed between the treatment arms
• Children completing this study had the opportunity to enroll in a global, open-label, multicenter, long-term extension study, in which they were able to either continue receiving or switch to Somatrogon^© Approximately 95% of the patients switched into the open-label extension study and received Somatrogon^© treatment

Phase 3 adults Somatrogon^© completed

• Primary endpoint of change in trunk fat mass from baseline to 26 weeks did not demonstrate a statistical significance between the Somatrogon^© treated group and placebo
• Completed post hoc outlier analysis in June 2017 to assess the influence of outliers on the primary endpoint results
• Analyses which excluded outliers showed a statistically significant difference between Somatrogon^© and placebo on the change in trunk fat mass: additional analyses that did not exclude outliers showed mixed results
• No safety concerns
• OPKO and Pfizer have agreed that OPKO may proceed with a pre-BLA meeting with FDA to discuss a submission plan
• OPKO plans to carry out an additional study in adults using a pen device

Pediatric Somatrogon^© registration study in Japan- expected to be completed in Q1 2020

• 44 patients, comparison of weekly Somatrogon to daily growth hormone.
• Same pen device, dosage and formulation used in global study.

Somatrogon^© Path to Approval

• BLA submission in US anticipated second half of 2020
  • Completion of analysis of immunogenicity and safety data from pivotal Phase 3 study and open label extension study
• Two abstracts accepted for oral presentation of data set at the Endo Society’s Annual Meeting in March 2020
  • “Somatrogon^© Growth Hormone in the Treatment of Pediatric Growth Hormone Deficiency: Results of the Pivotal Phase 3”
  • “Interpretation of Insulin-like Growth Factor (IGF-1) Levels Following Administration of Somatrogon^© (a long acting Growth Hormone-hGH-CTP)”
• MAA submission in Europe to follow upon completion of open label study demonstrating benefit and compliance with reduced treatment burden
  • Study expected to be completed in Q3 2020

References

Hershkovitz O, Bar-Ilan A, Guy R, et al. In vitro and in vivo characterization of MOD-4023, a long-acting carboxy-terminal peptide (CTP)-modified human growth hormone. Mol Pharm. 2016; 13:631–639 [PDF]

Strasburger CJ, Vanuga P, Payer J, et al. MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults. Eur J Endocrinol. 2017;176:283–294 [PDF]

Zelinska N, Iotova V, Skorodok J, et al. Long-acting CTP-modified hGH (MOD-4023): results of a safety and dose-finding study in GHD children. J Clin Endocrinol Metab. 2017;102:1578–1587 [PDF]

Fisher DM, Rosenfeld RG, Jaron-Mendelson M, et al. Pharmacokinetic and pharmacodynamic modeling of MOD-4023, a long-acting human growth hormone, in GHD Children. Horm Res Paediatr. 2017;87:324–332 [PDF]

Kramer W, Jaron-Mendelson M, Koren R, et al. Pharmacokinetics, Pharmacodynamics and Safety of a Long-Acting Human Growth Hormone (MOD-4023) in Healthy Japanese and Caucasian Adults. Clin Pharmacol Drug Dev. 2017 [in press]

Society and culture

Legal status

On 16 December 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ngenla, intended for the treatment of growth hormone deficiency (GHD) in children and adolescents from 3 years of age.^[3] The applicant for this medicinal product is Pfizer Europe MA EEIG.^[3]

Somatrogon was approved for medical use in Australia in November 2021.^[1]

References

1. ^ Jump up to:^a b c d “Ngenla”. Therapeutic Goods Administration (TGA). 13 December 2021. Retrieved 28 December 2021.
2. ^ Jump up to:^a b “Pfizer and OPKO Announce Extension of U.S. FDA Review of Biologics License Application of Somatrogon for Pediatric Growth Hormone Deficiency” (Press release). Opko Health. 24 September 2021. Retrieved 18 December 2021 – via GlobeNewswire.
3. ^ Jump up to:^a b “Ngenla: Pending EC decision”. European Medicines Agency (EMA). 16 December 2021. Retrieved 18 December 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

Further reading

• Fisher DM, Rosenfeld RG, Jaron-Mendelson M, Amitzi L, Koren R, Hart G (2017). “Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children”. Horm Res Paediatr. 87 (5): 324–32. doi:10.1159/000470842. PMC 5637306. PMID 28399519.

External links

• “Somatrogon”. Drug Information Portal. U.S. National Library of Medicine.

///////////Somatrogon, NGENLA, APPROVALS 2022, JAPAN 2022, ソマトロゴン , MOD-4023, Modigene, OPKO Health,  Pfizer