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

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• Niemann-Pick Disease, Type A 10

Niemann-Pick Disease, Type A

10 studies on the registry are indexed under Niemann-Pick Disease, Type A; 1 is open to participants now.

Lead sponsor

Genzyme, a Sanofi Company is the lead sponsor of 308 studies on the registry; 5 are open to participants now.

Of its 25 completed or terminated interventional studies of FDA-regulated products, 19 (76%) have results posted.

First submitted after Genzyme became part of Sanofi.

Study arms

• Experimental
  Olipudase alfa

  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

Interventions

• DrugOlipudase alfa

  Pharmaceutical form: powder for concentrate for solution for infusion Route of administration: intravenous infusion

  Also known as: GZ402665

Primary outcomes

1. 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).

   Time frame: From Baseline up to End of study (64 weeks)

2. 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.

   Time frame: Within up to 24 hours after start of any infusion (during the treatment period i.e. from Baseline up to 64 weeks)

3. 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.

   Time frame: Baseline, Week 52 (last complete assessment)

4. 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.

   Time frame: Baseline, Week 52 (last assessment)

5. 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.

   Time frame: At End of Study (Week 64)

6. 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.

   Time frame: From Baseline up to End of Study (64 weeks)

7. 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.

   Time frame: From Baseline up to End of Study (64 weeks)

8. Change From Baseline in Safety Biomarker Level: High Sensitivity C Reactive Protein (hsCRP) at Week 64

   Time frame: Baseline, Week 64 (pre-infusion)

9. Change From Baseline in Safety Biomarker: Ceramide Level at Week 64

   Time frame: Baseline, Week 64 (pre-infusion)

10. Change From Baseline in Safety Biomarker: Iron at Week 64

    Time frame: Baseline, Week 64 (pre-infusion)

11. Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64

    Time frame: Baseline, Week 64 (pre-infusion)

12. Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24

    Time frame: Baseline, Week 24 (pre-infusion, last assessment)

13. Change From Baseline in Safety Biomarker: Calcitonin at Week 64

    Time frame: Baseline, Week 64 (pre-infusion)

14. Doppler Echocardiogram: Absolute Change From Baseline in Left Ventricular Ejection Fraction at Week 52

    Time frame: Baseline, Week 52 (last assessment)

15. 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.

    Time frame: From Baseline up to Week 64

16. 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.

    Time frame: Week 52 (last assessment)

Secondary outcomes

1. 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.

   Time frame: At the end of infusion of the first 3.0 mg/kg dose and at Week 52

2. Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa

   Cmax: maximum plasma concentration observed.

   Time frame: 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

3. 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.

   Time frame: 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

4. 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.

   Time frame: 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

5. 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.

   Time frame: 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

6. 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.

   Time frame: 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

7. Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa

   tmax: time to reach maximum plasma concentration observed.

   Time frame: 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

8. 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).

   Time frame: Baseline, Week 52 (last assessment)

9. 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.

   Time frame: Baseline, Week 52 (last assessment)

10. 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.

    Time frame: Baseline, Week 52 (last assessment)

11. 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.

    Time frame: Baseline, Week 52 (last assessment)

12. 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.

    Time frame: Baseline, Week 52 (last assessment)

13. 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.

    Time frame: Baseline, Week 52 (last assessment)

14. 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.

    Time frame: Week 52 (last assessment)

15. Percent Change From Baseline in Efficacy Biomarkers Level at Week 52

    Efficacy biomarkers included chitotriosidase, chemokine ligand 18 (CCL18), angiotensin-converting enzyme (ACE).

    Time frame: Baseline, Week 52

16. 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.

    Time frame: Baseline, Week 52

17. Percent Change From Baseline in Bone Biomarkers at Week 52

    Bone biomarkers included bone specific alkaline phosphatase, C-Telopeptide.

    Time frame: Baseline, Week 52

18. 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.

    Time frame: Baseline, Week 52 (last assessment)

19. 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.

    Time frame: Baseline, Week 52 (Pre- infusion)

Baseline characteristics

6 further baseline measures are reported on the registry.

Publications

• Diaz GA, Jones SA, Scarpa M, Mengel KE, Giugliani R, Guffon N, Batsu I, Fraser PA, Li J, Zhang Q, Ortemann-Renon C. One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency. Genet Med. 2021 Aug;23(8):1543-1550. doi: 10.1038/s41436-021-01156-3. Epub 2021 Apr 19. PubMed 33875845 ↗

Study documents

• Study protocol ↗ · Aug 21, 2017
• Statistical analysis plan ↗ · Nov 5, 2019

PDFs hosted by the registry, ClinicalTrials.gov.

Individual participant data

Plan to share: Yes — Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org