Safety and Efficacy Study of MOD-4023 to Treat Children With Growth Hormone Deficiency

A Phase 3, Open-Label, Randomized, Multicenter, 12-month, Efficacy and Safety Study of Weekly MOD-4023 Compared to Daily Genotropin® Therapy in Japanese Pre-pubertal Children With Growth Hormone Deficiency

Treatment of children with growth failure due to growth hormone deficiency (GHD).

Primary • To evaluate the efficacy and safety of weekly MOD-4023 administration compared to daily Genotropin® administration in Japanese pre-pubertal children with GHD.

Secondary

• To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) profiles of three different doses of MOD-4023 in Japanese pre-pubertal children with GHD.

This is a 12-month, open-label, randomized, active controlled, parallel group study comparing the efficacy and safety of weekly MOD-4023 to daily recombinant human growth hormone (r-hGH), Genotropin ®. Both drugs will be injected subcutaneously (SC) using a pen device.

After a 4 week Screening period, patients meeting all the entry criteria and none of the exclusion criteria, will be eligible to participate in the study.

Eligible patients will be randomized in a 1:1 ratio, to receive either:

• MOD-4023 (investigational treatment): weekly MOD-4023 SC injections for 12 months; initially over the first 6 weeks, MOD-4023 will be administered in 3 stepwise escalating doses (0.25 mg/kg/week, 0.48 mg/kg/week and 0.66 mg/kg/week), each for two weeks sequentially. For the remaining 46 weeks, patients will continue to receive MOD-4023 at a dose of 0.66 mg/kg/week.

Or

• Genotropin® (reference treatment): daily Genotropin® (0.025 mg/kg/day which is equivalent to 0.175 mg/kg/week, divided equally into 7 daily injections over a week) SC injection for 12 months.

After the 6-week PK/PD sampling period, the dose of MOD-4023 and Genotropin® will be adjusted every 3 months based on a patient's body weight. Doses may be decreased for safety reasons according to the pre-defined dose-adjustment criteria (which will be based on the severity of adverse events (AEs) or repeated, elevated levels of IGF-1 Standard Deviation Score (SDS)).

The key safety data will be reviewed by an independent and external Data and Safety Monitoring Board (DSMB). DSMB review will also include a review of the number or percentage of patients requiring dose reductions due to AEs. Following the completion of the12-month treatment period, eligible patients will be consented to enroll into an open-label long term extension (LTE) period, and an amendment to this study protocol will be submitted prior to the first patient completes the 12 months treatment period. Eligible Genotropin®-treated patients will be switched to a MOD-4023 dose of 0.66 mg/kg/week in the LTE. The LTE is planned to continue until MOD-4023 marketing registration in Japan.

Inclusion Criteria:

1. Pre-pubertal child aged ≥ 3 years old, and not yet 10 years for girls (9 years and 364 days) or not yet 11 years for boys (10 years and 364 days), on the date of ICF signature, with either isolated GHD, or GH insufficiency as part of multiple pituitary hormone deficiency.

2. Confirmed diagnosis of GHD by 2 different types of GH provocation tests (standardized on growth foundation data): defined as a peak serum GH level of ≤ 6.0 ng/mL or ≤ 16 ng/mL when conducting GHRP-2 provocation test.

   Prior local laboratory results will be accepted subject to pre-approval by the study medical monitor and if the tests were conducted as specified in the protocol.

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.

5. Height SD score ≤ -2.0 at screening

6. Impaired height velocity defined as:

   • Annualized height velocity (HV) below the 25th percentile for CA (HV < -0.7 SDS) and gender according to the local primary care provider standard.
   • The interval between two height measurements should be at least 6 months, but should not exceed 18 months prior to inclusion.

7. BMI must be within ±2 SDS of mean BMI for the chronological age and sex.

8. Baseline IGF-1 level of at least 1 SDS below the mean IGF-1 level standardized for age and sex (IGF-1 SDS ≤ -1) according to the central laboratory reference values. A single re-test will be allowed (subject to discussion with the study medical monitor) if all other criteria are met.

9. Normal creatinine levels according to common practice reference ranges per age.

10. 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 to ICF signing

11. Normal 46 XX karyotype for girls.

12. Willing and able to provide written informed consent of the parent or legal guardian of the patient and written assent from pediatric patients (when applicable based on age and Japan regulation).

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 suspected psychosocial dwarfism by the discretion of the investigator
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. Children with diabetes mellitus
9. Chromosomal abnormalities including Turner's syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, Russell-Silver syndrome, SHOX (short stature homeobox) mutations/deletions and skeletal dysplasia's, with the exception of septo-optic dysplasia.
10. Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids, sex steroids, with the exception of ADHD drugs or hormone replacement therapies (thyroxin, hydrocortisone, desmopressin [DDAVP])
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 as provided in Appendix J.
12. Major medical conditions and/or presence of contraindication to r-hGH treatment.
13. Known or suspected HIV-positive patient, or patient with advanced diseases such as AIDS or tuberculosis.
14. Drug substance or alcohol abuse.
15. Known hypersensitivity to the components of study medication.
16. Other causes of short stature such as celiac disease, uncontrolled primary hypothyroidism and rickets.
17. The patient and/or the parent/legal guardian are likely to be non-compliant in respect to study conduct.
18. Participation in any other clinical trial within 30 days prior to screening and throughout the entire study period (including administration of investigational agent).