Safety, Tolerability, PK, and Efficacy Evaluation of Repeat Ascending Doses of Olipudase Alfa in Pediatric Patients <18 Years of Age With Acid Sphingomyelinase Deficiency

Study Overview
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Brief Summary
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Primary Objective: To evaluate the safety and tolerability of olipudase alfa administered intravenously in pediatric participants every 2 weeks for 64 weeks. Secondary Objective: To characterize the pharmacokinetic profile and evaluate the pharmacodynamics and exploratory efficacy of olipudase alfa administered intravenously in pediatric participants every 2 weeks for 64 weeks.

Detailed Description
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The maximum study duration per participant was approximately 18 months (screening period: up to 60 days; treatment period: 64 weeks; post-treatment period: up to 37 days, not applicable if participants enrolled in a long-term extension treatment trial).

Official Title
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A Phase 1/2, Multi-Center, Open-Label, Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Exploratory Efficacy of Olipudase Alfa in Pediatric Patients Aged <18 Years With Acid Sphingomyelinase Deficiency

Conditions
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Sphingomyelin Lipidosis

Intervention / Treatment
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* Drug: Olipudase alfa


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : The participant and/or participant's parent(s)/legal guardian(s) must provide written informed assent/consent prior to any protocol-related procedures being performed. The participant was <18 years of age on the date of informed assent/consent. The participant had documented deficiency of acid sphingomyelinase as measured in peripheral leukocytes, cultured fibroblasts, or lymphocytes. The participant had a spleen volume greater than or equal to (>=) 5 multiples of normal (MN) measured by magnetic resonance imaging (MRI); participants who had partial splenectomy were allowed if the procedure was performed >=1 year before screening and the residual spleen volume was >=5 MN. The participant's height was -1 Z-score or lower. A negative serum pregnancy test in female participants of childbearing potential. Female participants of childbearing potential and male participants must be willing to practice true abstinence in line with their preferred and usual lifestyle or use 2 acceptable effective methods of contraception. Exclusion criteria: The participant had received an investigational drug within 30 days before study enrollment. The participant had any of the following medical conditions: An active, serious, intercurrent illness. Active hepatitis B or hepatitis C infection. Infection with human immunodeficiency virus (HIV). Cirrhosis (determined by clinical evaluation). Significant cardiac disease (eg, clinically significant arrhythmia, moderate or severe pulmonary hypertension or valvular dysfunction, or <40 percent (%) left ventricular ejection fraction by echocardiogram). Malignancy diagnosed within the previous 5 years (except basal cell carcinoma). Any other extenuating circumstance that can significantly interfere with study compliance, including all prescribed evaluations and follow-up activities. The participant had acute or rapidly progressive neurological abnormalities. The participant was homozygous for SMPD1 gene mutations R496L, L302P, and fs330 or any combination of these 3 mutations. The participant had a delay of gross motor skills. The participant had a major organ transplant (eg, bone marrow, liver). The participant required use of invasive ventilatory support. The participant required use of noninvasive ventilatory support while awake and for greater than (>)12 hours a day. The participant in the investigator's opinion, was unable to adhere to the requirements of the study. The participant had a platelet count <60 × 10^3/µL (based on the average of 2 screening samples obtained up to 24 hours apart). The participant had alanine aminotransferase or aspartate aminotransferase >250 IU/L or total bilirubin >1.5 mg/dL. The participant had an international normalized ratio (INR) >1.5. The participant was unwilling or unable to abstain from ingesting alcohol the day before through 3 days after each infusion of olipudase alfa during the treatment period. Measuring alcohol concentration in blood was not required. The participant was scheduled during the study for in-patient hospitalization including elective surgery. The participant required medication(s) that may can decrease olipudase alfa activity (eg, fluoxetine, chlorpromazine; tricyclic antidepressants [eg, imipramine, or desipramine]). The participant was breast-feeding. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olipudase alfa<br>Participants received intravenous (IV) infusion of olipudase alfa once every 2 weeks (Q2W) for 64 weeks. Each participant underwent a dose escalation according to the following paradigm: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0 milligram per kilogram (mg/kg). Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 64 treatment weeks. | Drug: Olipudase alfa<br>* Pharmaceutical form: powder for concentrate for solution for infusion Route of administration: intravenous infusion<br>* Other names: GZ402665;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs were defined as adverse events (AEs) that occurred or worsened during the on-treatment period (time from the start of investigational medicinal product [IMP]) administration until end of study (i.e. up to 64 weeks). | From Baseline up to End of study (64 weeks) | 
| Number of Participants With Infusion-Associated Reactions (IARs) | IARs were defined as AEs that occurred during the infusion or within up to 24 hours after the start of infusion and were considered as related or possibly related to the study treatment by the investigator or the sponsor. Protocol-defined IAR: all AEs that were identified as an IAR by the investigator. Events occurring greater than or equal to (>=) 24 hours after the start of an infusion might had been judged an IAR at the discretion of the investigator or sponsor. | Within up to 24 hours after start of any infusion (during the treatment period i.e. from Baseline up to 64 weeks) | 
| Number of Participants With Change in Physical Examination | Change from Normal assessment (at Baseline) to Abnormal assessment (at Week 52) was reported. Physical examinations included following observations/measurements: examination of the skin, head, eyes, ears, nose, and throat; lymph nodes; heart, lungs, and abdomen; extremities and joints. Abnormality in physical examinations was based on investigator's discretion. | Baseline, Week 52 (last complete assessment) | 
| Number of Participants With Change in Neurological Examination | Change from Normal assessment (at Baseline) to Abnormal assessment (at Week 52) was reported. Neurological examination included: coordination examination, cranial nerve examination, extrapyramidal features, fundoscopy, gait and coordination examination, motor examination, tone peripheral nervous system, reflexes examination, sensory examination, strength examination, mental status. | Baseline, Week 52 (last assessment) | 
| Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | Abnormal values in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and alkaline phosphatase were reported. | At End of Study (Week 64) | 
| Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | Heart Rate (HR) High: >=120 beats per minute (bpm) (adolescents), >=120 bpm (children), >=140 bpm (early children), >=175 bpm (infants) & increase from baseline (IFB) >=20 bpm for all age categories. HR Low: <=50 bpm (adolescents), <=50 bpm (children), <=75 bpm (early children), <=80 bpm (infants) & decrease from baseline (DFB) >=20 bpm for all age categories. Systolic BP (SBP) High: >=119 mmHg (adolescents), 108 mmHg (children), 101 mmHg (in early children), 98 mmHg (infants) & IFB >=20 mmHg for all age categories. SBP Low: <=90 mmHg (adolescents), <= 80mm Hg (children), <=70 mmHg (early children), <=70 mmHg (infants) & DFB >=20 mmHg for all age categories. Diastolic BP (DBP) High:>=78 mmHg (adolescents), >=72 mmHg (children), >=59 mmHg (in early children), >=54 mmHg (infants) & IFB >=10 mmHg for all age categories. DBP Low:<=54 mmHg (adolescents), <=48 mmHg (children), <=34 mmHg (early children), <=34 mmHg (infants) & DFB >=10 mmHg for all age categories. | From Baseline up to End of Study (64 weeks) | 
| Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | Criteria for potentially clinically significant ECG abnormalities: High PR Interval: >=180 milliseconds (ms) in adolescents, 170 ms in children, 160 ms in early children, and 140 ms in infants; High QRS Interval: >=110 ms in adolescents, 100 ms in children, 95 ms in early children and 85 ms in infants; Prolonged QTc Fridericia (QTc F): >450 ms in male adolescents, children, early children and infants or 470 ms in female adolescents, QTc F >500 ms; QTc F increase from baseline >60 ms. | From Baseline up to End of Study (64 weeks) | 
| Change From Baseline in Safety Biomarker Level: High Sensitivity C Reactive Protein (hsCRP) at Week 64 |  | Baseline, Week 64 (pre-infusion) | 
| Change From Baseline in Safety Biomarker: Ceramide Level at Week 64 |  | Baseline, Week 64 (pre-infusion) | 
| Change From Baseline in Safety Biomarker: Iron at Week 64 |  | Baseline, Week 64 (pre-infusion) | 
| Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64 |  | Baseline, Week 64 (pre-infusion) | 
| Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24 |  | Baseline, Week 24 (pre-infusion, last assessment) | 
| Change From Baseline in Safety Biomarker: Calcitonin at Week 64 |  | Baseline, Week 64 (pre-infusion) | 
| Doppler Echocardiogram: Absolute Change From Baseline in Left Ventricular Ejection Fraction at Week 52 |  | Baseline, Week 52 (last assessment) | 
| Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Serum samples for immunogenicity assessment were analyzed to detect ADA. ADA response were categorized as: treatment emergent antibody i.e. treatment-induced/treatment-boosted response. A participant whose ADA status was positive anytime post-baseline and was negative or missing at baseline was considered to have treatment induced ADA. A participant whose ADA status was positive at baseline (pre-existing ADA) and the ADA titer level anytime post-baseline was significantly higher than that at baseline is considered to have treatment boosted ADA. Positive samples in the ADA assay were further analyzed in the NAb assay as positive NAb inhibition of catalytic activity and positive NAb inhibition of cellular uptake. | From Baseline up to Week 64 | 
| Number of Participants With Abnormalities in Liver Ultrasound Doppler at Week 52 | Evidence of portal hypertension was assessed by portal vein direction from liver ultrasound doppler. | Week 52 (last assessment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi) | Ceoi was defined as the plasma concentration at the end of infusion (EOI). Data collected for child and Infant/child age groups at 0-30 min from end of infusion was considered at end of infusion. | At the end of infusion of the first 3.0 mg/kg dose and at Week 52 | 
| Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa | Cmax: maximum plasma concentration observed. | Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52 | 
| Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUClast: Area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to the time of last measured concentration. AUC(0-tau): area under the plot of the drug concentration versus the time curve from time 0 to the end of the dosing interval (tau), where dosing interval was 2 weeks. | Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52 | 
| Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa | Half-life is the time measured for the plasma concentration of drug to decrease by one half. | Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52 | 
| Pharmacokinetic Parameter: Total Body Clearance (CL) of Olipudase Alfa | Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Total body clearance of a drug from the plasma calculated using equations below: CL = Dose / AUC after the first dose. | Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52 | 
| Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. | Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52 | 
| Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa | tmax: time to reach maximum plasma concentration observed. | Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52 | 
| Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52 | Spleen and liver volumes was assessed by abdominal magnetic resonance imaging (MRI). | Baseline, Week 52 (last assessment) | 
| Change From Baseline in Interstitial Lung Disease Score Measured Using High Resolution Computed Tomography (HRCT) at Week 52 For Both Lungs | Pulmonary imaging of chest using HRCT was obtained to quantitate the degree of possible infiltrative lung disease. Lung fields were assessed by a central reader & scored subjectively for the degree of interstitial lung disease on a scale ranges from 0 =normal, 1 =mild, 2=moderate and 3 =severe, where higher scores indicate more severity. | Baseline, Week 52 (last assessment) | 
| Change From Baseline in Height Z-Scores at Week 52 | Z-score for height of participants was evaluated. Height Z-Score, i.e., the height-for-age Z Score, is the number of standard deviations of the actual height of a child from the median height of the children of the corresponding age and sex as determined from the standard sample. A height Z-score of 0 is equal to the median and is considered normal. Negative numbers indicate values lower than the median and positive numbers indicate values higher than the median. For analysis, mean Z-score was calculated and an increase of mean height Z-score from baseline indicates an improvement on growth. | Baseline, Week 52 (last assessment) | 
| Percent Change From Baseline in Percent Predicted Hemoglobin-Adjusted Diffusing Capacity of Carbon Monoxide (DLco) at Week 52 | Percent predicted Hemoglobin-adjusted DLco was calculated as: 100*Adjusted DLco/Predicted DLco in unit of mL CO/min/mmHg where, adjusted DLco = Observed DLco (in mL CO/min/mmHg) divided by Hemoglobin-adjusted factor. Per planned analysis, pulmonary function testing (PFT) was to be performed only on participants >=5 years of age therefore, data for participants in age cohort: infant/early child were not collected. | Baseline, Week 52 (last assessment) | 
| Change From Baseline in Difference Between Actual Age and Bone Age of Participants at Week 52 | Hand X-ray was performed on participant's left hand, fingers and wrist to assess bone age of participants. At each visit (Baseline and Week 52), difference between the bone age and actual age at that visit was calculated. Difference in age in months was calculated as bone age in months minus real age at time of assessment (in months) at specified time points. In this outcome measure change from baseline at Week 52 in the difference between actual age and bone age (in months) is reported. | Baseline, Week 52 (last assessment) | 
| Change From Baseline in Cycle Ergometry: Maximum Workload at Week 52 | Cardiopulmonary status was assessed using a stationary one-wheeled cycle used as an ergometer to measure a person's work output under controlled conditions. Participants were asked to ride the cycle at increasing workload levels until they could no longer proceed. The workload at which participant stopped and cannot proceed was considered as maximum workload (in watt). As per the planned analysis, this assessment was not to be performed on participants that were <=6 years of age or <120 cm in height on day 1/week 0, therefore infant/early child cohort was not evaluable. | Baseline, Week 52 (last assessment) | 
| Physician's Global Assessment of Participant's Progress: Observed Scores at Week 52 | Physician assessed participant's current clinical status (refers to clinical status at Week 52 in comparison to Baseline) was evaluated by marking 1 of the following 7 categories: • marked improvement, • moderate improvement, • mild improvement, • no change, • mild worsening, • moderate worsening, or • marked worsening. These 7 categories were converted to scores as follows: 3 = marked improvement of daily activities, 2 = moderate improvement of daily activities, 1 = mild improvement of daily activities, 0 = no change, -1 = mild worsening of daily activities, -2 = moderate worsening of daily activities, -3 = marked worsening of daily activities where higher score indicated improvement in daily activities as compared to baseline. In this outcome measure, observed scores of participant's clinical status at Week 52 are reported. | Week 52 (last assessment) | 
| Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | Efficacy biomarkers included chitotriosidase, chemokine ligand 18 (CCL18), angiotensin-converting enzyme (ACE). | Baseline, Week 52 | 
| Percent Change From Baseline in Lipid Profile at Week 52 | Lipid profile parameters included low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol and triglycerides. | Baseline, Week 52 | 
| Percent Change From Baseline in Bone Biomarkers at Week 52 | Bone biomarkers included bone specific alkaline phosphatase, C-Telopeptide. | Baseline, Week 52 | 
| Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | PedsQL includes a child self-report (CS-R) for participants 5 to 18 years and parents' report (PR) of participants 2 to 18 years. CS-R: 23-item PedsQL Generic Core Scales report includes 4 scales, Physical (P), Emotional (E), Social (S), and School Functioning (SF). PR: 21-item PedsQL Generic Core Scales report includes P, E, S, and SF scales. Each item used a 5-point rating scale ( from 0=never to 4=almost always). Items are reverse scored and linearly transformed to a 0 (almost always) -100 (never) scale. Higher score indicates better Health Related Quality of Life (HRQoL). P, E, S and SF summary scores are calculated as mean of respective functioning items. Psychosocial Health Summary Score is calculated as mean of 13 or 15 items (E, S and SF). Generic core total scale score is calculated as the mean of all the 21 or 23 items (P, E, S and SF). All summary/total scores are mean of specific items and they all have values ranges from 0 to 100, where higher score=better HRQoL. | Baseline, Week 52 (last assessment) | 
| Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52 | Sphingomyelin and Lyso-sphingomyelin levels were assessed in plasma. Lyso-sphingomyelin is a metabolite of sphingomyelin. | Baseline, Week 52 (Pre- infusion) |