Diagnosis of short stature updates

and long acting growth hormones

Dr.Goran Mohammad
 Lonapegsomatropin(Skytrofa) a long-acting GH therapy
(LAGH),composed of somatropin with the same 191 aminoacid
sequence and molecular weight (22KDa,) was approved by the
United States Food and Drug Administration in August 2021 for
the treatment of pediatric growth hormone deficiency (GHD).

 Lonapegsomatropin is a prodrug consisting of unmodified GH

transiently conjugated to methoxypolyethylene glycol which
enables time-release of GH with a half-life of ~25 hours allowing
for once weekly administration.

 Lonapegsomatropin is distributed in temperature-stable, prefilled

cartridges at 9 different doses that can be prescribed based upon
specific weight brackets designed to deliver approximately 0.24
mg/kg/wk.
history
 GH therapy for children with GH deficiency (GHD) began in 1958 with
the use of pituitary derived human GH that was administered by
intramuscular injection three times per week
 The first attempt at developing a LAGH preparation was performed in
1979 by Lippe et al by incorporating pituitary derived human GH into
gelatin to prolong its half-life.
 Subsequently, recombinant human GH (rhGH) therapy was administered
daily and became available for the treatment of pediatric GHD (PGHD)
in 1985 and adult GHD (AGHD) in 1996.
 However, because of the need for daily injections, the adherence to GH
has shown to decrease over time with concomitant reductions in height
velocity and insulinlike growth factor I (IGF-I) levels in the short term in
children and adolescents
 It is likely that reduced adherence to daily injections limits treatment
outcomes as evidenced by adult height in children who required GH
replacement therapy that are below the mean for the population
Mechanism of Action
 Lonapegsomatropin is a sustained-release inactive prodrug
consisting of unmodified GH transiently bound to an inert
carrier {methoxypolyethylene glycol (mPEG)}, via a
proprietary linker.

 The prodrug is absorbed from the subcutaneous injection site

into the circulation and acts as a circulatory reservoir.

 The linker undergoes autohydrolysis under physiologic pH

and temperature, releasing fully active GH at the GH receptor.
The inert carrier is primarily cleared by renal excretion.

 The mPEG carrier is cleared primarily by renal filtration and to

a minor extent by hepatobiliary excretion.
Pharmacokinetics
Absorption: subcutaneous tissue
The large peak of lonapegsomatropin that occurs
within the first 24 hours following subcutaneous
administration.
The half-life of lonapegsomatropin is 30.7 ± 12.7
hours, while the half-life of released GH is
approximately 25 hours and the apparent clearance of
lonapegsomatropin is 3.2 mL/h/kg in pediatric
patients.
This contrasts to the half-life of approximately 20- 30
minutes for DGH after a subcutaneous
administration.
The pharmacodynamics of lonapegsomatropin
have been measured using IGF-I
It is necessary that the timing of the injection
and the timing of collection of the serum
sample are known in order to calculate the
estimated average IGF-I level.
the peak IGF-I level occurs at approximately
2.5 days and the average IGF-I level occurs at
approximately four days.
Therefore, if a convenience sample is obtained
four days after the injection, it is a reasonable
estimate of the average IGF-I. If the sample is
collected at any other time following the
injection, the IGF-I calculator can be used to
calculate the estimated average IGF-I. Because
the shape of the pharmacodynamic curve
should be identical regardless of the method of
IGF-I assay, the IGF-I calculator could be very
useful regardless of the type of IGF-I assay
used
Dose Adjustment
 Lonapegsomatropin has been studied in clinical trials using a weight-based
dosing at a dose of 0.24 mg/kg/wk.

 Not use below 1 year of age and weight less than 11.5 kg

 The use of IGF-I levels to guide dose adjustment has been recommended for
both safety and shortterm efficacy purposes.

 Therefore, it will be important to be able to estimate an average IGF-I from

serum samples collected at random clinic visits. Using the IGF-I calculator to
estimate average IGF-I values from these samples may help guide dose
adjustment of lonapegsomatropin

 Growth velocity with LAGH is 11.2cm/yr in comparison to DGH which is

10.3cm/yr
Patient Selection for
Lonapegsomatropin
Potential candidates for lonapegsomatropin include
 individuals with poor adherence particularly teenagers
 young children expected to be on therapy for many
years
 children with needle phobia
 children transitioning to self-injection
 patients on multiple other medications, particularly
injectable medications like insulin.
 The cost and cost-effectiveness of lonapegsomatropin
and other LAGH products is also likely to impact
treatment decisions.
Contraindications
 Acute critical illness after open heart surgery, abdominal surgery,
multiple accidental traumas, or those with acute respiratory failure
 Hypersensitivity to somatropin
 Closed epiphyses
 Active malignancy, owing to risk of malignancy progression
 Active proliferative or severe nonproliferative diabetic retinopathy
 Prader-Willi syndrome who are severely obese, have a history of
upper airway obstruction or sleep apnea, or have severe
respiratory impairment
 Undiagnosed or untreated hypothyroidism may prevent optimal
treatment response
 May decrease insulin sensitivity, particularly at higher doses;
previously undiagnosed impaired glucose tolerance and overt type
2 diabetes mellitus (DM) may be unmasked
use with caution
in children with severe GHD associated with
hypoglycemia may not be good candidates for
lonapegsomatropin or other LAGH products
since they may be at increased risk of
hypoglycemia.
Somatropin increases growth rate, and
progression of existing scoliosis can occur in
patients who experience rapid growth;
somatropin has not been shown to increase
occurrence of scoliosis; monitor patients with a
history of scoliosis for disease progression
Side Effects
 Nausea, vomiting, diarrhea, abdominal pain, or joint pain
 development of a limp, hip/knee pain, numbness/tingling, increased thirst/
frequent urination, swelling hands/ankles/feet,
 signs of bleeding (such as nosebleeds, small red or purple spots on the
skin),
 Thyroid disorder:hypothyroidism
 may increase your risk of tumor.
 Children who have had brain/head radiation treatment for cancer should
be monitored for new tumors/cancers.
 Slipped capital femoral epiphysis
 Pancreatitis reported; consider pancreatitis in patients who develop
persistent severe abdominal pain
 When somatropin is administered SC at same site over a long period,
tissue atrophy may result; avoid by rotating injection site
 Intracranial hypertension (IH) with papilledema, visual changes,
headache, nausea, and/or vomiting reported
Drug interaction

 Replacement glucocorticoid treatment

◦ Patients treated with glucocorticoid replacement for
hypoadrenalism may require an increase in their
maintenance or stress dose following initiation
◦ Initiating lonapegsomatropin may result in inhibition
of 11βHSD-1 and reduced serum cortisol
concentrations
◦ Microsomal enzyme 11β-hydroxysteroid
dehydrogenase type 1 (11βHSD-1) is required for
conversion of cortisone to its active metabolite,
cortisol, in hepatic and adipose tissue
 Cytochrome P450-metabolizing drugs
◦ Carefully monitor when used in combination with drugs
metabolized by cytochrome P450 (CYP450) liver enzymes,it
alter clearance of compounds metabolized by this enzymes
 Oral estrogen
◦ Patients receiving oral estrogen replacement may require higher
lonapegsomatropin dosages
◦ Oral estrogens may reduce the serum insulinlike growth factor-
1 response to lonapegsomatropin
 Insulin and/or other antihyperglycemic agents
◦ Patients with diabetes mellitus may require dosage adjustment
of their insulin and/or other antihyperglycemic agents
◦ Lonapegsomatropin may decrease insulin sensitivity,
particularly at higher doses
Thank you