Safety and Efficacy Phase 3 Study of Long-acting hGH (MOD-4023) in Growth Hormone Deficient Children

The study consists of a 12 month, open-label, randomized, active controlled, parallel group study comparing the efficacy and safety of weekly MOD-4023 to daily growth hormone (GH), Genotropin. After 12 months, subjects will have the option to enter the long term open-label extension.

• MOD-4023 (Drug), also known as Somatrogon: Once weekly subcutaneous injection using pre-filled pen device.
• Somatropin (Drug), also known as Genotropin: Once daily subcutaneous injection of Genotropin using pre-filled pen device.

Primary outcomes

• Annual Height Velocity in Main Study Phase [52 weeks]: Annual Height Velocity in cm. Annual Height Velocity at 12 months is based on the difference between the heights at 12 months and baseline.
• Annual Height Velocity in OLE Phase [Up to 60 months]: Annualized Height Velocity (cm/year) in OLE Phase

Secondary outcomes

• Height Velocity at 6 Months in Main Study Phase [After 6 months of treatment]: Height velocity in cm measured after 6 months of treatment. Annualized Height velocity after 6 months is calculated based on the difference between the heights at 6 months and baseline.
• Change in Height Standard Deviation Score (SDS) in Main Study Phase [After 6 and 12 months]: Change in height Standard Deviation Score (SDS) after 6 and 12 months is calculated based on the difference between the heights at 6 and 12 months and baseline.
• Change in Bone Maturation (BM) in Main Study Phase [52 weeks]: Annual change in bone age measurements as per Gruelich-Pyle method
• Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in Main Study Phase [Baseline and at 12 months]: Via central lab analysis
• Change in Height Standard Deviation Score (SDS) in OLE Phase [60 months]: Change in height Standard Deviation Score (SDS) at each time point is calculated based on the difference between the time point and baseline.
• Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase [60 Months]

Other outcomes

• Device [6 weeks]: Proportion of successful single injections out of total number of single injections using the MOD-4023 Pen in the USA
• Device [1 week]: Proportion of successful single injections out of total number of single injections using the MOD-4023 Pen in the USA at Week 1 based on the Observer Assessment Tool (OAT)

Sex: All, ages: 3 Years to 11 Years

Main Study Inclusion Criteria:

1. Pre-pubertal children aged ≥3 years, and not yet 11 years for girls or not yet 12 years for boys with either isolated GHD, or GH insufficiency as part of multiple pituitary hormone deficiency.
2. Confirmed diagnosis of GHD by two different GH provocation tests defined as a peak plasma GH level of ≤10 ng/mL.
3. Bone age (BA) is not older than chronological age and should be less than 10 for girls and less than 11 for boys.
4. Without prior exposure to any r-hGH therapy (naïve patients).
5. Impaired height and height velocity defined as:

   * Annualized height velocity (HV) below the 25th percentile for CA (HV < -0.7 SDS) and gender according to sponsor calculator
   * The interval between 2 height measurements should be at least 6 months, but should not exceed 18 months prior to inclusion
6. Baseline IGF-1 level of at least 1 SD below the mean IGF-1 level standardized for age and sex (IGF-1 SDS ≤-1)
7. Normal calculated GFR per updated bedside Schwartz formula for pediatric patients.
8. Children with multiple hormonal deficiencies must be on stable replacement therapies (no change in dose) for other hypothalamo-pituitary-organ axes for at least 3 months prior ICF signing.
9. Normal 46XX karyotype for girls.
10. Willing and able to provide written informed consent of the parent or legal guardian and written assent from patient.

    LT-OLE Inclusion Criteria:
11. Completion of the main study (12 months of treatment) with adequate compliance.
12. Willing and able to provide written informed consent of the parent or legal guardian and written assent from patient.
13. Agree to refrain from sexual activity.

Main Study Exclusion Criteria:

1. Children with prior history of leukemia, lymphoma, sarcoma or any other forms of cancer.
2. History of radiation therapy or chemotherapy.
3. Malnourished children defined as BMI < -2 SDS for age and sex.
4. Children with psychosocial dwarfism.
5. Children born small for gestational age (SGA - birth weight and/or birth length <-2 SDS for gestational age).
6. Presence of anti-hGH antibodies at screening.
7. Any clinically significant abnormality likely to affect growth or the ability to evaluate growth, such as, but not limited to, chronic diseases like renal insufficiency, spinal cord irradiation, etc.
8. T2 and T1 diabetic patients, who in the opinion of the investigator are not receiving standard of care treatment or are non-compliant with their prescribed treatment or who are in poor metabolic control.
9. Chromosomal abnormalities including Turner's syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, Russell-Silver syndrome, SHOX mutations/deletions and skeletal dysplasias.
10. Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids, or sex steroids, with the exception of ADHD drugs or hormone replacement therapies (thyroxin, hydrocortisone, desmopressin).
11. Children requiring glucocorticoid therapy (e.g. for asthma) that are taking chronically a dose greater than 400 μg/d of inhaled budesonide or equivalent.
12. Major medical conditions and/or presence of contraindication to r-hGH treatment.
13. More than one closed epiphyses.
14. Known or suspected HIV-positive patient, or patient with advanced diseases such as AIDS or tuberculosis.
15. Drug, substance, or alcohol abuse.
16. Known hypersensitivity to the components of study medication.
17. Other causes of short stature such as celiac disease, uncontrolled primary hypothyroidism and rickets.
18. Likely non-compliance in respect to study conduct.
19. Participation in any other trial of an investigational agent within 30 days prior to consent.
20. Study enrollment has been met or study is closed by sponsor prior to completion of screening process.

    LT-OLE Exclusion Criteria:
21. Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids, or sex steroids, with the exception of ADHD drugs or HRT (thyroxin, hydrocortisone, desmopressin).
22. Change in medical condition during the treatment period (such as, but not limited to, development of a serious inter-current critical illness, a severe adverse drug reaction, etc.).
23. Positive pregnancy test.
24. Unresolved drug related (Genotropin or MOD-4023) SAE from the treatment period as per medical monitor judgement.

Participant flow

Outcome results

• Annual Height Velocity in Main Study Phase (Primary), Least squares mean, cm/year: MOD-4023 10.10 (9.58 to 10.63); Genotropin 9.78 (9.29 to 10.26)
• Annual Height Velocity in OLE Phase (Primary), Mean, cm/year: MOD-4023 10.27 +/- 2.38; Genotropin 9.72 +/- 2.50
• Height Velocity at 6 Months in Main Study Phase (Secondary), Least squares mean, cm/year: MOD-4023 10.59 (9.96 to 11.22); Genotropin 10.04 (9.47 to 10.62)
• Change in Height Standard Deviation Score (SDS) in Main Study Phase (Secondary), Mean, Standard Deviation Score: MOD-4023 0.54 (0.48 to 0.61); Genotropin 0.48 (0.42 to 0.54)
• Change in Bone Maturation (BM) in Main Study Phase (Secondary), Mean, ratio of bone age to chronologic age: MOD-4023 0.05 +/- 0.09; Genotropin 0.06 +/- 0.1
• Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in Main Study Phase (Secondary), Mean, Standard Deviation Score (SDS): MOD-4023 -1.95 +/- 0.89; Genotropin -1.72 +/- 0.90
• Change in Height Standard Deviation Score (SDS) in OLE Phase (Secondary), Mean, Standard Deviation Score: MOD-4023 -2.95 +/- 1.30; Genotropin -2.79 +/- 1.31
• Insulin-like Growth Factor-1 (IGF-1) Standard Deviation Score (SDS) in OLE Phase (Secondary), Mean, Standard Deviation Score: MOD-4023 77.91 +/- 46.11; Genotropin 83.10 +/- 41.17
• Device (Other pre specified)
• Device (Other pre specified), Count of participants, Participants: MOD-4023 17

Adverse events

Time frame: 1 year for Main Study Phase. Up to 6 years for OLE Phase.

Serious adverse events by term

Other adverse events by term

19 more terms not shown.

• Results publication: Gomez R, Khadilkar V, Shembalkar J, Chu DM, Ko CW, Wajnrajch MP, Wang R. Post hoc subgroup analysis of Asian children with paediatric GHD from the global phase 3 efficacy and safety study of once-weekly somatrogon vs. once-daily somatropin. J Pediatr Endocrinol Metab. 2024 May 9;37(6):525-531. doi: 10.1515/jpem-2023-0512. Print 2024 Jun 25. PMID 38717038
• Results publication: Loftus J, Quitmann J, Valluri SR. Health-related quality of life in pre-pubertal children with pediatric growth hormone deficiency: 12-month results from a phase 3 clinical trial of once-weekly somatrogon versus once-daily somatropin. Curr Med Res Opin. 2024 Feb;40(2):175-184. doi: 10.1080/03007995.2023.2290623. Epub 2024 Jan 24. PMID 38053515
• Results publication: Gomez R, Lamoureux R, Turner-Bowker DM, Loftus J, Maghnie M, Miller BS, Polak M, Yaworsky A. Physician experience with once-weekly somatrogon versus once-daily rhGH regimen in pediatric patients with growth hormone deficiency: a cross-sectional survey of physicians from the global phase 3 study. Front Endocrinol (Lausanne). 2023 Oct 17;14:1254424. doi: 10.3389/fendo.2023.1254424. eCollection 2023. PMID 37955005
• Results publication: Deal CL, Steelman J, Vlachopapadopoulou E, Stawerska R, Silverman LA, Phillip M, Kim HS, Ko C, Malievskiy O, Cara JF, Roland CL, Taylor CT, Valluri SR, Wajnrajch MP, Pastrak A, Miller BS. Efficacy and Safety of Weekly Somatrogon vs Daily Somatropin in Children With Growth Hormone Deficiency: A Phase 3 Study. J Clin Endocrinol Metab. 2022 Jun 16;107(7):e2717-e2728. doi: 10.1210/clinem/dgac220. PMID 35405011

• Study Protocol (PDF, 2018-04-27)
• Statistical Analysis Plan (PDF, 2024-01-03)

• Tony Cruz, Study director, Sponsor GmbH