Trial Investigating the Efficacy and Safety of Weekly Lonapegsomatropin Compared to Daily Somatropin in Children and Adolescents With Short Stature or Growth Failure Due to Growth Hormone Sufficient Disorders

Inclusion Criteria:

1. Chronological age between ≥2 and <18 years, at start of screening.

2. Naïve to growth hormone and growth hormone promoting therapies.

3. Prepubertal.

4. Able to stand without assistance.

5. Diagnosis of TS, SHOX-D, SGA, or ISS with impaired growth or short stature,according to the following disease-specific criteria: TS or SHOX-D (Léri-Weill dyschondrosteosis):

6. Diagnosis confirmed by a genetic test. NOTE: Historical test results areacceptable for proof of diagnosis. For karyotypes, a minimum of 20 cells mustbe counted.

7. Impaired growth or short stature defined as:

(i.) AHV <25th percentile over a time span of 6-16 months prior to screeningutilizing a historical height properly documented in a health care setting (self-measurement record is not accepted) OR (ii.) Height <5th percentile for sexand age according to the Centers for Disease Control Growth Charts for the UnitedStates SGA without catch-up growth: c. Birth weight and/or birth length < -2.0 SDS for gestational age according to the 2006 World Health Organization Child Growth Standards. For infants born premature,the Fenton Preterm Infant Growth Chart (Fenton 2013) should be used. d. Impaired growth or short stature defined as: (i.) AHV <25th percentile over atime span of 6-16 months prior to screening properly documented in a health caresetting (self-measurement record is not accepted) OR (ii.) Height < -2.0 SDS for ageand sex according to the 2000 Centers for Disease Control Growth Charts for theUnited States for children ≥ 3 years or height < -2.5 SDS for age and sex accordingto the for children ≥ 2 years and < 3 years ISS: e. Height < -2.25 SDS for sex and age according to the Centers for Disease ControlGrowth Charts for the United States with no identifiable cause for short stature. f. Documented normal GH-IGF-1 axis, defined as either: (i.)IGF-1 SDS >0 at screeningbased on central laboratory OR (ii.)Historical documentation of normal peak GH uponstimulation test (as defined by local institution) g. 46,XX chromosome as determinedby karyotype or microarray if female. For karyotypes, a minimum of 30 cells must becounted.

6. If on hormone replacement therapies for any hormone deficiencies other than growthhormone (e.g., adrenal, thyroid), must be on adequate and stable doses for ≥4 weeksprior to and throughout screening.

7. Written, signed informed consent provided by parent(s) or legal guardian(s) of theparticipant. Assent should be signed by participant as required by IRB/HREC/IEC.

Exclusion Criteria:

1. Advanced bone age X-ray by central reading defined as >20% above chronological agein months (Greulich 1959).

2. Closed epiphyses as defined as bone age of ≥14.0 years in females or ≥16.0 years inmales.

3. Current clinical diagnosis of diabetic retinopathy

4. Any diagnosis or presence at screening of the following:

5. Untreated moderate or severe sleep apnea as determined by formal (local) readof an inpatient or at-home sleep study.

6. Prader Willi syndrome with severe obesity, history of severe upper airwayobstruction, or severe respiratory impairment.

7. Signs/symptoms of intracranial hypertension, active proliferative retinopathy.

8. Uncontrolled hypo- or hyperthyroidism.

9. Uncontrolled diabetes mellitus (defined as: HbA1c >7.5% from central laboratory atscreening).

10. Known history or diagnosis of any gastrointestinal inflammatory condition, HIV,radiation exposure, other skeletal dysplasias, growth hormone deficiency, and/orcardio-thoracic surgery due to their independent effects on growth.

11. Any significant hepatic or renal abnormality, such as abnormal renal function (defined as eGFR <60 mL/min/1.73m2).

12. Undiagnosed or uncontrolled hypertension.

13. Receiving treatment with any agent that might influence growth or interfere with GHsecretion or action including any sex steroids and stimulants forattention-deficit/hyperactivity disorder (ADHD).

14. High dose inhaled glucocorticoid for more than 28 consecutive days total over thecourse of 12 months.

15. Female who is pregnant, plans to be pregnant, or breastfeeding.

16. Participation in another interventional clinical trial involving an investigationalcompound within 90 days prior to screening or in parallel to this trial.

17. Any disease or condition that, in the judgement of the investigator, may make theparticipant unlikely to comply with the requirements of the protocol or anycondition that presents undue risk from the investigational product or trialprocedures.

18. Exclusion Criteria only applicable to TS:

19. Presence of Y chromosome material on genetic testing without history ofgonadectomy.

20. Less than 10% of 45,X mosaicism.

21. Any known, clinically significant, congenital or acquired cardiovasculardysfunction that might interfere with growth.

22. Exclusion Criteria only applicable to SGA: a. Any known clinically significant abnormality likely to affect growth or theability to evaluate growth with standing height measurements: (i.)Chromosomalaneuploidy, significant gene mutations, or medical syndromes with short stature,including but not limited to Turner syndrome, Laron syndrome, Noonan syndrome,Prader-Willi syndrome, abnormal SHOX-1 gene analysis or absence of GH receptors.

(ii.)Congenital abnormalities (causing skeletal abnormalities), including but notlimited to skeletal dysplasias.

18. Exclusion Criteria only applicable to ISS:

19. Known history of any condition that causes disproportionate short stature (i.e.skeletal dysplasias), chromosomal aneuploidy, significant gene mutations, ormedical syndromes with short stature, including but not limited to Turnersyndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, abnormalSHOX-1 gene analysis or absence of gH receptors.