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

NCT02292654 | Completed Phase 1 Results DMC

• 2 other identifiers: DFI13803U1111-1160-6469
• Study Type: interventional
• Target: 20
• Locations: 6 countries
• Sites: 6

Brief Summary

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.

Conditions

Sphingomyelin Lipidosis

Outcome Measures

Primary Outcomes (16)

• 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 Outcomes (19)

• Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi)

  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

  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

  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

  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

  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

Study Arms (1)

Olipudase alfa

EXPERIMENTAL

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

Olipudase alfa DRUG

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

Also known as: GZ402665

Olipudase alfa

Eligibility Criteria

• Age: Up to 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (6)

Investigational Site Number 840001

New York, New York, 10029, United States

Location

Investigational Site Number 076001

Porto Alegre, 90035 003, Brazil

Location

Investigational Site Number 250002

Bron, 69677, France

Location

Investigational Site Number 276001

Mainz, 55131, Germany

Location

Investigational Site Number 380001

Udine, 33100, Italy

Location

Investigational Site Number 826001

Manchester, M13 9WL, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 33875845 DERIVED

MeSH Terms

Conditions

Niemann-Pick Disease, Type A

Interventions

olipudase alfa

Condition Hierarchy (Ancestors)

Niemann-Pick Diseases; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 7, 2014
• First Posted: November 17, 2014
• Study Start: May 1, 2015
• Primary Completion: December 9, 2019
• Study Completion: December 9, 2019
• Last Updated: March 23, 2022
• Results First Posted: February 1, 2021

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share

Locations

IT (1); FR (1); US (1); BR (1); GB (1); DE (1)