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Somatrogon

Also known as Ngenla, somatrogon-ghla, MOD-4023, OPKO-4023

Weekly growth hormone fused to three hCG C-terminal peptides, for growth hormone deficiency in children.

clinically proven Growth hormone approved drug

At a glance

Category
Growth hormone
Status
approved drug
Made from
recombinant A fusion protein produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology 1.
Route
subcutaneous injection once weekly, on the same day each week, into the abdomen, thighs, buttocks or upper arms with weekly site rotation
Half-life
an effective half-life of about 37.7 hours in children with growth hormone deficiency, estimated by population pharmacokinetics; somatrogon remains in the circulation for roughly 8 days after the last dose 1
Onset
serum concentrations rise slowly, peaking 6 to 25 hours after a dose with a median of 11 hours; IGF-1 peaks around 2 days post-dose, with the average weekly IGF-1 occurring around 4 days post-dose 1
Molecular weight
approximately 40 kDa 1
Sequence
The human growth hormone sequence carrying one copy of the C-terminal peptide (CTP) of the beta chain of human chorionic gonadotropin at the N-terminus and two tandem copies at the C-terminus

Prescription-only biological medicine. Approved by the FDA on 27 June 2023 under BLA 761184 6 for children aged 3 years and older with growth failure due to inadequate secretion of endogenous growth hormone 1. The EU marketing authorisation was issued on 14 February 2022, also for children and adolescents from 3 years of age 2. Unlike somapacitan and lonapegsomatropin, somatrogon has no adult growth hormone deficiency indication in either jurisdiction.

Doping status: Prohibited at all times (WADA S2.2.3, named)

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Expression in a mammalian cell line rather than in E. coli is not incidental: the C-terminal peptide's half-life-extending effect depends on O-linked glycosylation, which bacteria cannot perform.

Mechanism of action

Somatrogon binds the growth hormone receptor and initiates the same signal transduction cascade as growth hormone itself, activating STAT5b and raising serum IGF-1, which together drive linear growth and the metabolic changes associated with GH 1. The receptor pharmacology is unremarkable; the engineering is in the tail.

The half-life extension is borrowed from another human hormone. Chorionic gonadotropin and luteinising hormone share an alpha chain and have closely related beta chains, but hCG persists in the circulation far longer — the difference is a 28-amino-acid C-terminal peptide on the hCG beta chain that carries four O-linked, heavily sialylated glycans. Those negatively charged sugars slow renal clearance and shield the protein from proteolysis. Somatrogon carries three copies of that peptide, one at the N-terminus and two in tandem at the C-terminus, which takes a 22 kDa hormone to roughly 40 kDa and stretches its effective half-life to about 37.7 hours 1.

Three approved weekly growth hormones now solve the same problem three different ways, and the contrast is the most useful thing to hold on to. Somapacitan attaches a small albumin-binding side chain and rides on the patient's own albumin. Lonapegsomatropin is a prodrug: unmodified somatropin is conjugated to a large PEG carrier by a linker that cleaves itself at a fixed rate, so what reaches the receptor is plain growth hormone. Somatrogon takes the glycopeptide-tail approach. The strategies differ in what the patient is chronically exposed to — albumin binding, PEG polymer, or a large fusion protein — and that difference shows up in the immunogenicity data.

Somatrogon is by some distance the most immunogenic of the three. In the 12-month main period of the pivotal trial, 84 of 109 treated children (77.1%) tested positive for anti-drug antibodies, most with specificity to human growth hormone, and the antibodies persisted in most of those children. Neutralising antibodies appeared in 8 of 217 children (3.7%) over up to 42 months and were transient in every case. Neither binding nor neutralising antibodies had a clinically significant effect on safety or effectiveness over 12 months, and no effect on growth was seen across a further 30 months of extension 1. Antibody-positive children had roughly 26% lower apparent clearance, which the label does not consider clinically significant 1. The comparison with lonapegsomatropin, at 6.3% binding antibodies and none neutralising, is stark — but 'stark' and 'clinically consequential' are different claims, and the data so far support only the first.

As with the other weekly products, somatrogon replaces the nocturnal pulsatility of endogenous growth hormone with a single weekly rise and fall. IGF-1 levels stay within the normal range for children with GHD over the week, comparably to daily somatropin 1; whether the shape of the exposure matters over a decade of paediatric treatment is not something the registration programme could answer.

What the research shows

The registration evidence is a single well-conducted randomised, open-label, active-controlled phase 3 trial against daily somatropin, showing non-inferiority on annualised height velocity at 52 weeks, supported by extension data. Regulatory review in the US and EU has been favourable. The endpoint is a surrogate for adult height, the follow-up is short relative to a paediatric treatment course, and there is no head-to-head trial against the other weekly products.

Research in humans

The pivotal trial (NCT02968004) randomised 224 treatment-naive prepubertal children with growth hormone deficiency to somatrogon 0.66 mg/kg per week (n=109) or daily somatropin 0.034 mg/kg per day (n=115). At week 52 the annualised height velocity was 10.1 cm/year on somatrogon against 9.8 cm/year on daily somatropin, a difference of 0.3 cm/year (95% CI -0.2 to 0.9); the mean increase in height standard deviation score was 0.92 and 0.87 respectively 13. Safety was broadly comparable except at the injection site, where reactions were reported by 42.2% of the somatrogon group against 25.2% of those on daily somatropin — injection site pain 39% versus 25%, swelling or induration 10% versus 1%, erythema 8% versus none, pruritus 5% versus none 1. That is a striking difference given that somatrogon is injected once a week and the comparator seven times a week.

Animal and lab research

No long-term carcinogenicity studies and no genotoxicity studies have been performed with somatrogon 1. In rats, somatrogon lengthened the oestrous cycle and copulatory interval and increased the number of corpora lutea at exposures 22-fold the maximum recommended human dose and above, without affecting female fertility, mating indices, embryo numbers or early embryonic development, and without affecting male fertility up to 45-fold the human dose on an exposure basis 1. The neoplasm warnings on the label are inherited from the somatropin class.

Caveats. One pivotal trial, 52 weeks, with annualised height velocity as the endpoint — a surrogate for the adult height that actually matters. The trial and its extensions are manufacturer-sponsored. There is no adult indication and no adult efficacy dataset comparable to those supporting somapacitan and lonapegsomatropin. The 77.1% anti-drug antibody rate is unusually high for a growth hormone product; it has not so far translated into a loss of effect, but the follow-up published to date covers a few years of what is typically a decade-long treatment. Excretion was not evaluated in clinical studies, and somatrogon has not been studied in hepatic or renal impairment 1.

What it is used for

  • Growth failure in children aged 3 years and older due to inadequate secretion of endogenous growth hormone — the sole approved indication in both the US and the EU 12
  • There is no approved indication in adults with growth hormone deficiency, and none for the non-deficiency paediatric indications (small for gestational age, Turner syndrome, idiopathic short stature) that daily somatropin and somapacitan carry
  • Non-medical use for body composition or athletic performance is not a licensed use, is unsupported by evidence, and is prohibited in sport — somatrogon is named on the WADA Prohibited List 5

Dosing

Dose
0.66 mg/kg body weight once weekly
Frequency
once weekly, on the same day each week, at any time of day
Route
subcutaneous, into the abdomen, thighs, buttocks or upper arms with weekly site rotation
Duration
Treatment continues until the epiphyses close, as with other growth hormone products used for growth promotion in children.
  • This figure comes from the FDA-approved product information 1 and describes treatment of diagnosed paediatric growth hormone deficiency under specialist supervision. It is not a protocol and not advice.
  • There is no titration. The dose follows body weight and is individualised on growth response 1.
  • The maximum a single injection can deliver is 12 mg from the 24 mg pen and 30 mg from the 60 mg pen. Above that the weekly dose is split across two injections at different sites 1; the EU overview notes this applies to patients over about 45 kg needing more than 30 mg 2.
  • Patients switching from daily growth hormone may start weekly somatrogon on the day after their last daily injection 1.
  • The 0.66 mg/kg per week figure looks far larger than the 0.16 mg/kg for somapacitan or the 0.24 mg/kg for lonapegsomatropin, and it is not comparable to either. Somatrogon is a 40 kDa fusion protein, so a milligram of it contains proportionally much less growth hormone; lonapegsomatropin doses are stated in somatropin equivalents. The three numbers are not on the same scale and cannot be converted into one another.
  • Dosing is in milligrams, not International Units. Figures circulating for grey-market growth hormone are quoted in IU and do not transfer to this product.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Ngenla — children with growth hormone deficiency

approved product information

Source: NGENLA (somatrogon-ghla) FDA prescribing information

Every week, same day0.66 mg/kg actual body weight once weekly, subcutaneously
Doses above the pen maximumsplit into two injections at different sites — the 24 mg pen delivers at most 12 mg per injection and the 60 mg pen at most 30 mg
Ongoingindividualised on growth response

A single fixed weight-based dose with no titration schedule. Patients switching from daily growth hormone can begin the day after their last daily injection. A fundoscopic examination is performed before starting and periodically thereafter, and treatment is stopped if papilloedema develops.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes
24 mg/1.2 ml (20 mg/ml) single-patient-use prefilled pen, dialling in 0.2 mg increments to a maximum of 12 mg per injection, 60 mg/1.2 ml (50 mg/ml) single-patient-use prefilled pen, dialling in 0.5 mg increments to a maximum of 30 mg per injection
Storage
Refrigerated at 2-8 °C in the original carton to protect from light before first use, and refrigerated between uses thereafter for up to 28 days. Do not freeze or shake; do not use if frozen. Keep away from heat and direct sunlight. Write the date of first use on the pen label and discard 28 days after it.

Worked example

Not applicable. Somatrogon is supplied as a ready-to-use preserved solution in a prefilled multidose pen; nothing is reconstituted or calculated. The dose is dialled directly in milligrams. Where the weekly dose exceeds what one injection can deliver, it is given as two injections at separate sites rather than by adjusting the concentration.

The solution contains metacresol as a preservative, which is why a multidose pen is possible at all, and which is relevant to anyone with a known cresol sensitivity. Remove and discard the needle after each injection and store the pen without a needle attached. Do not use if the solution is not clear and colourless to slightly light yellow.

This is not reconstituted from a powder — it is supplied as a ready-made solution, or as a kit that mixes to a single fixed dose. The vial-and-solvent arithmetic used elsewhere on this site does not apply.

Safety

Side effects

  • Injection site reactions, the most common adverse reaction and the one that most clearly separates somatrogon from daily somatropin in the head-to-head trial: 42.2% versus 25.2%, comprising injection site pain (39% versus 25%), swelling, induration, hypertrophy or inflammation (10% versus 1%), erythema (8% versus none), pruritus (5% versus none) and haemorrhage (5% versus none) 1
  • Nasopharyngitis (33%), headache (16.5%), pyrexia (16.5%), anaemia (9.2%), cough (8.3%), vomiting (7.3%), hypothyroidism (6.4%), abdominal pain (6.4%), rash (5.5%) and oropharyngeal pain (5.5%) 1
  • Fluid retention, which may be dose-dependent and may require a dose reduction 1
  • Reduced insulin sensitivity, particularly at higher doses; glucose is monitored periodically in all patients and more closely in those with or at risk of diabetes 1
  • Intracranial hypertension. Fundoscopy is performed before starting and periodically thereafter, and treatment is stopped if papilloedema occurs 1
  • Hypoadrenalism may be unmasked or worsened, with a possible need for higher glucocorticoid maintenance or stress doses 1
  • Hypothyroidism may become evident or worsen; thyroid function is monitored periodically 1
  • Slipped capital femoral epiphysis — a new limp or persistent hip or knee pain should be evaluated — and development or progression of scoliosis 1
  • Pancreatitis, to be considered in anyone with persistent severe abdominal pain 1
  • Lipoatrophy at repeatedly used injection sites, which is why sites are rotated 1
  • Severe hypersensitivity reactions may occur, including anaphylaxis and angioedema 1
  • Increased risk of a second neoplasm in childhood cancer survivors treated with growth hormone, particularly meningiomas after radiation to the head; patients with pre-existing tumours are monitored for progression or recurrence 1
  • Anti-drug antibodies in 77.1% of treated children over 12 months, persisting in most, with transient neutralising antibodies in 3.7% over up to 42 months and no clinically significant effect on safety or effectiveness observed to date 1

Do not use if

  • Acute critical illness, because of the increased mortality reported with growth hormone after open-heart surgery, abdominal surgery, multiple accidental trauma or in acute respiratory failure 1
  • Hypersensitivity to somatrogon or to any excipient 1
  • Closed epiphyses 1
  • Active malignancy 1
  • Active proliferative or severe non-proliferative diabetic retinopathy 1
  • Prader-Willi syndrome in children who are severely obese or have severe respiratory impairment 1
  • Somatrogon has not been studied in hepatic or renal impairment 1

Interactions

Patients on glucocorticoid replacement for hypoadrenalism may need an increase in maintenance or stress doses once somatrogon is started, and in children on pharmacologic or supraphysiologic glucocorticoid therapy the glucocorticoid dose is adjusted to avoid both hypoadrenalism and an inhibitory effect on growth 1. Growth hormone may alter the clearance of drugs metabolised by cytochrome P450 enzymes. Insulin and other antihyperglycaemic agents may need dose adjustment, since growth hormone decreases insulin sensitivity 1. Somatostatin analogues such as octreotide and lanreotide, and the GH receptor antagonist pegvisomant, oppose the same axis pharmacologically. The label reports no formal drug interaction studies specific to somatrogon.

Sources