1 Principal Investigator was changed to read Coordinating Investigator 2 Maximum number of participating countries updated 3 Rotation of the injection site updated 4 The Screening period was extended to six weeks 5 The assessment for anti-MOD-4023 Abs removed from Screening 6 Clarify the stratification 7 Assessment of Baseline MOD-4023 (Cohorts 1-3) 8 An HbA1c assessment was added to Visits 4, 11, 12 9 Protocol was amended to remove inclusion criterion number 5 10 The interval between two HT measurements was clarified 11 Karyotype testing was specified to be performed by central laboratory 12 The planned PK/PD analyses were amended 13 Clarify that MOD-4023 was tested in adults in a Phase II 14 The allocation of identification numbers was clarified 16 Assessment of parameters of glucose metabolism in Genotropin patients, at Visits 2 and 4 added 17 Clarify that Lp(a) assessment will be done only at Visit 6 18 Clarify that the final visit will occur four days (-1) after the last MOD-4023 dose for Cohorts 1-3 and the day after the last Genotropin dose for Cohort 4 19 Clarify that predicted adult age will be calculated for children above seven years 20 Coordinating Investigator will approval the use of thyroid replacement therapy 21 Clarify that deviations in the weekly dosing during the PK/PD period will be considered as major 22 Clarify that the reporting of SAEs will be done electronically 23 Change in the contact person for SAE reporting 24 Address the possibility of measurement of cortisol levels is a glucagon stimulation test was historically 25 Clarify that both GH-stimulation tests were not required to have been conducted by the central laboratory 26 Clarify that a screening, and not a Baseline adrenocorticotropic hormone (ACTH) test will be done 27 Clarify that a cubital vein will be used for the ACTH test 28 Replace the Wong-Baker image for local pain 29 list the names of the central technical facilities and contractors was amende

No patients were enrolled at the time this amendment was issued 1. Redefine the content of the study drug through the addition of “growth hormone” or “protein” where applicable. 2. Clarification was made on sex hormone priming 3. The protocol was amended to modify the expression of the doses in the in the three MOD- 4023 cohorts due to a change in the calculation of content of the drug. 4. The protocol was amended to include the possibility accepting results from historical sex hormone stimulation testing to avoid the need to retest children in a short time frame. At least one of the two tests, however, must be retested at the central laboratory and as such, reserve samples must have been retained at the original testing facility. If a patient requires both stimulation tests during Screening, it is recommended that testing be performed on two consecutive days. 5. The definition of malnourishment was clarified to be inclusive of all three indicating factors: serum albumin below LLN according to the reference ranges of the central laboratory, serum iron below the LLN according to reference ranges of the central lab, and BMI<-2SD for age and sex. 6. Clarify the primary efficacy endpoint of annual HV in cm/year at 12 months 7. Correct the molecular weight of the IP to correctly read ~38,330 Daltons (Da). 8. Change the lowest chosen dose of MOD-4023 due to the modified content of the IP. 9. Clarify that the primary endpoint is Annual HV at 12 months. 10. Clarify that all patients, regardless of the MOD-4023 cohort to which they are assigned, will begin treatment at the lowest dose. Dose levels will then be increased in a step wise manner until the maximum dose is obtained. 11. Define the assay that will be used for IGF-1 assessment. 12. Protocol was amended to describe the procedure of sex hormone priming that will be performed prior to GH-stimulation tests

At the time this amendment was issued eight patients had been treated. 1. Protocol was amended to include additional sites. 2. Distribution of study population to address change in inclusion criteria 2: Patients will be divided into two subgroups: Up to 40 patients with ppGH levels after stimulation test ≤7 ng/ml and up to 16 patients with ppGH levels after stimulation test >7 and ≤10 ng/ml. 3. The protocol was amended to address change in ppGH level to address the known common practice in newly added countries and already participating sites in the study. 4. Protocol was amended to address change in study population; sub-groups of ≤7 ng/ml and > 7 ng/ml and ≤ 10 ng/ml. 5. The protocol was amended to reflect the current practice for glucagon testing to avoid unnecessary side effects. 6. The list of central laboratories was updated. 7. The protocol was amended to clarify the analysis of efficacy: a. The efficacy analysis will be performed based upon the FAS and PP subsets and subgroups based on peak hGH level following stimulation tests. 8. Protocol was amended to clarify GH stimulation tests and other assessments would be performed per the 2000 Growth Hormone Research Society Consensus Guidelines. 9. The glucagon test was amended to reflect the current practice for the test and to avoid unnecessary side-effects for the patients.

At the time of this amendment 32 patients had been treated. 1. The protocol was amended to address a change concerning stratification factors since the previous ones resulted in an unequal distribution of patients with regards to [HTSDS - target HTSDS] and ppGH levels. Including this new factor, all new patients will be randomized using the same dynamic minimization rule while considering the following stratification factors and using the allocation of the existing patients as the baseline for determining the allocation of new patients. Moreover, this will neither modify the allocation of existing patients, nor create a situation where a patient that would have been eligible based on the inclusion/exclusion criteria will not be included solely based on the randomization parameters, nor the Investigator’s ability to predict the next dose allocation (and therefore his judgment whether to include a patient in the study or not). All eligible patients will be enrolled per protocol. 2. The protocol was amended to address a change to mistakenly specified dose levels of lower dose cohorts (change to 0.48 and 0.66 from 0.31 and 0.60). This was an editorial change to the protocol to clarify the doses that were actually taken. 3. The protocol was amended to address a change within section “Contact persons and numbers” and mistakenly left wrong address. 4. Visit schedule was updated to reflect ≤six weeks acceptable for Screening.

At the time of this amendment, 53 patients had been treated. 1. Amendment done to focus and highlight inclusion criteria for the OLE study 2. The duration of the OLE was clarified as being expected to run for a 12 month duration. 3. The process for distributing MOD-4023 to patients in the OLE was clarified 4. Address the change in stratification methodology to the dynamic minimization method. Further stratification for ppGH levels (≤2, 2 < ppGH ≤7) was introduced such that patients with ppGH levels >7-10 were permitted to be enrolled, however, these patients would have a separate randomization list. 5. Fully describe the OLE period including decisions regarding assessment of eligibility, randomization, allocation of study drug, and study visit design. 6. Clarification made within the protocol, the reference to last visit refers only to the Main Study and does not include the OLE. When all patients have completed the Main Study,a full-analysis (CSR) will be performed based on the SAP. When all patients complete the second year of treatment, an additional analysis will be performed. 7. The protocol was amended to clarify that dose efficacy will be analyzed after 12 months of treatment on a per patient basis. Patients who had not successfully achieved the minimally satisfactorily growth rate were moved to the next higher dose level. 8. Specify the dose level that will be used in the OLE period. 9. Specify randomization for the Main Study and OLE such that all patients will receive MOD-4023 either at the dose level they had received during the Main Study, or will be randomized to one of the three MOD-4023 cohort if they had been receiving placebo during the Main Study. 10. Specify the way of analyzing the dose and efficacy within both Main Study and OLE; dose efficacy will be analyzed again after 12 months of treatment on an individual patient level. 11. The list of central laboratories was updated.

The following changes were made to the protocol: • The protocol was amended to remove the study site “Bulgaria” from the extension study. • Updated the duration of the main study from 24 months to 12 months for each subject and the OLE period was based on the initial extension of 12 months of active treatment for all subjects completing the main study which was extended on a yearly basis until marketing approval in each country. • Study design and procedures were revised to indicate that all subjects who completed 12 months of the main study and those who were already in the LT-OLE period were eligible to continue in the extension study until marketing approval in their country, subject to an annual notification to local IEC/IRB continuation of the study. In both cases, subjects were to sign the new assent and/or ICD. • OLE was divided into first year extension with 12 months continuous repeated dosing of somatrogon. Provided dose reduction paradigm based on IGF-1 SDS for subjects switching to 0.66 mg/kg/week somatrogon. • Clarification was added that the end of study was identical to Visit 12 of the main study regardless of whether the subject was in main study or the OLE Study. • Included OLE efficacy endpoints. • The dosing and storage instructions for the IP were revised. • Text was revised to indicate that interim analysis was to be performed after 80% to 100% of the subjects had completed 6 months of the treatment. • Administrative changes included addition of OPKO name and logo throughout the document and change in signatories.

This amendment was approved internally at OPKO prior to the implementation of all relevant changes and not submitted to regulatory authorities or operationally implemented.

The following changes were made to the protocol: • The study design was revised to switch all subjects from Cohorts 1 and 2 entering the LT-OLE period (Period IV) to somatrogon 0.66 mg/kg/week. • The OLE Period was split into two periods: OLE (Period III) and LT-OLE (Period IV) until marketing approval in each country. The study visits and assessments for the LT-OLE period were revised. • Text was revised to delete the conduct of interim analysis. • The protocol was amended to clarify that the DSMB was to meet approximately every 6 months or on an ad-hoc basis in case of any safety concerns during the OLE or LT-OLE periods. • The name of Drug Safety contact was updated. • Pregnancy was added under AE as a potential reason for discontinuation from the study. • Administrative changes consisted of minor clarifications, change in General Manager name, corrections of inconsistencies between sections of the protocol, glossary update, choice of words, redundancies deletion, update to Appendices 2 and 3 to reflect changes in study procedures, correction of typographical errors, and logistical clarifications.

The following changes were made to the protocol: • The study design was amended to include PEN period (Period V) until marketing approval in their country, subjected to an annual notification to local IEC/IRB of continuation of study, where applicable. Specific criteria for PEN period was added in inclusion/exclusion criteria and efficacy/secondary endpoints were added in the protocol. • Transition from test drug vials to use of the pen was added in this protocol amendment. Instructions for the use of the pen and dose modification were added along with IP maintenance. • This protocol amendment provided clarification for switching to higher dose of 0.66 mg/kg/week. • Information for pregnancy and ECG assessments were included as per regulatory and United States Food and Drug Administration requirements. • Administrative changes included details about transition of the study protocol to Veeva eTMF and change of Sponsor address and staff. Details of vice president of Clinical Development along with details of medical officer were added in the protocol.