A Long-Term Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency

NCT02004704 | Completed Phase 2 Results DMC

• 2 other identifiers: LTS136322013-000051-40
• Study Type: interventional
• Target: 25
• Locations: 7 countries
• Sites: 9

Brief Summary

The primary objective of this study was to obtain data regarding the safety of olipudase alfa in participants with acid sphingomyelinase deficiency (ASMD) who were exposed to long term treatment with olipudase alfa. The secondary objectives of this study were to obtain data regarding the efficacy of olipudase alfa and to characterize olipudase alfa pharmacodynamics (PD) and pharmacokinetics (PK) following long-term administration.

Conditions

Sphingomyelin Lipidosis

Outcome Measures

Primary Outcomes (16)

• Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs) and Adverse Events of Special Interest (AESIs) Except Infusion-Associated Reactions (IARs)

  An AE: Any untoward medical occurrence in participant or clinical investigation participant administered with pharmaceutical product, which did not necessarily have to have causal relationship with study treatment. SAEs: Any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect, was medically important event. TEAEs: AEs that started during on-treatment period-either in this study or in original study which were ongoing at the time the participant signed the written informed consent. An AESI: AE (serious or nonserious) of scientific and medical concern specific to sponsor's product or program, for which ongoing monitoring and rapid communication by investigator to sponsor was appropriate.

  From the signature of informed consent up to 9 years or until olipudase alfa was commercially accessible, whichever came first

• Number of Participants With IARs

  Protocol-defined IARs were 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. Events occurring greater than or equal to (\>=) 24 hours after the start of an infusion might have been judged an IAR at the discretion of the investigator or sponsor. Algorithm-defined IARs were all AEs that started between the start of infusion and the end of infusion plus 24 hours, irrespective of the perceived relation with study treatment.

  From the signature of informed consent up to 9 years or until olipudase alfa was commercially accessible, whichever came first

• For Adults: Number of Participants With Abnormality in Complete Physical Examinations Including Abbreviated Physical Exam

  A complete physical examination included assessment of the participant's general appearance, general neurological status, skin, head, eyes, ears, nose, throat, lymph nodes, heart, lungs, abdomen, and extremities/joints. Shift from Baseline was monitored. An abbreviated physical exam (general appearance only) was only performed pre- and post-infusion for those who did not do complete exam.

  Baseline (Day 1 of original study), Month 78

• For Pediatrics: Number of Participants With Abnormality in Complete Physical Examinations Including Abbreviated Physical Exam

  A complete physical examination included assessment of the participant's general appearance, skin, head, eyes, ears, nose, throat, lymph nodes, heart, lungs, abdomen, and extremities/joints. Shift from Baseline was monitored. An abbreviated physical exam (general appearance only) was only performed pre- and post-infusion for those who did not do complete exam.

  Baseline (Day 1 of original study), Month 84

• For Adults: Number of Participants With Abnormality in Extended Neurological Examinations

  Extended neurological examination for adults included examination of mental status. Shift from Baseline was monitored.

  Baseline (Day 1 of original study), Month 78

• For Pediatrics: Number of Participants With Abnormality in Extended Neurological Examinations

  The neurological examination in pediatric participants included examination of mental status, cranial nerve examination, motor examination: tone, reflexes examination, sensory examination, coordination, gait and coordination, and strength examination. Shift from Baseline was monitored.

  Baseline (Day 1 of original study), Month 84

• Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Vital Signs

  PCSA: Heart Rate: High: \>=120 beats per minute (bpm) (adults \[ad\], adolescents \[ado\], children \[chi\]), \>=140 bpm (early chi \[ec\]), \>=175 bpm (infants\[inf\]) \& increase from baseline (IFB)\>=20 bpm for all age ranges (AAR), HR Low: \<=50 bpm (ad, ado, chi), \<=75 bpm (ec), \<=80 bpm (inf) \& decrease from baseline (DFB) \>=20 bpm for AAR. Systolic blood pressure: High: \>= 160 millimeters of mercury (mmHg) (ad); \>=119 mmHg (ado), \>=108 mmHg (chi), \>=101 mmHg (ec),\>=98 mmHg (inf) \& IFB \>=20 mmHg for AAR. SBP Low: \<=95 mmHg (ad), \<=90 mmHg (ado), \<= 80mm Hg (chi), \<=70 mmHg (ec), \<=70 mmHg (inf) \& DFB \>=20 mmHg for AAR. Diastolic blood pressure: High:\>110 mmHg (ad), \>=78 mmHg (ado), \>=72 mmHg (chi), \>=59 mmHg (ec), \>=54 mmHg (inf) and IFB \>=10 mmHg for AAR. DBP Low:\<=45 mmHg (ad), \<=54 mmHg (ado), \<=48 mmHg (chi), \<=34mmHg (ec and inf) \& DFB\>=10 mmHg for AAR.

  Baseline (Day 1 of original study) up to 9 years or until olipudase alfa was commercially accessible, whichever came first

• Number of Participants With PCSA in Clinical Chemistry Parameters

  PCSA: Creatinine High, category 1: \>=150 micromole/L (umol) (adults), \>=132 umol/L or 1.5 mg/deciliter (dL) (adolescents), \>=90 umol/litre (L) or 1.1 mg/dL (children), \>53 umol/L or 0.6 mg/dL (early children and infants); category 2: \>=30% IFB (adults). Blood Urea Nitrogen: \>=17 millimole (mmol)/L (adults), \>=6.4 mmol/L or 18 mg/dL (pediatrics \[ped\]). Glucose Low\<=3.9 mmol/L and \<lower limit of normal (adults), \<2.7 mmol/L (ped), High: \>=11.1 mmol/L (unfasted), \>7 mmol/L (fasted) (adults), \>=7 mmol/L (fasted after \>12 hours of fast); \>=10.0 mmol/L (unfasted) (ped).

  Baseline (Day 1 of original study) up to 9 years or until olipudase alfa was commercially accessible, whichever came first

• Number of Participants With PCSA in Liver Function Tests

  PCSA: Alanine aminotransferase (ALT) \>3 x upper limit of normal (ULN). Aspartate aminotransferase (AST) \>3 x ULN. Alkaline phosphatase (ALP) \> 1.5 x ULN. Total Bilirubin \>1.5 x ULN (ad) and \>1.3 x ULN (ped). ALT and total bilirubin: ALT \> 3 x ULN and total bilirubin \> 2 x ULN.

  Baseline (Day 1 of original study) up to 9 years or until olipudase alfa was commercially accessible, whichever came first

• Number of Participants With PCSA in Hematology Parameters

  PCSA: White blood cells (WBC): Low: \<3.0 Giga (G)/L (Non-Black \[NB\])/\<2.0 G/L (Black \[B\])(ad), \<4.5 G/L (ado), \<5.0 G/L(chi), \<3.0 G/L (ec), \<4.0 G/L (inf), High: \>=16.0 G/L(ad), \>13.5 G/L (ado), \>17.0 G/L(chi), \>16 G/L (ec), \>20 G/L (inf). Hemoglobin-ad: Low-1: \<=115 g/dL (Male \[M\])/\<=95 g/dL (Female \[F\]), 20% DFB for both, High:\>=185 g/L (M)/\>=165 g/L (F), Low-2: DFB\>=20 g/L (ad), \<10 g/dL (ado, chi, ec); \<9.0 g/dL (inf); 20% DFB for all. Platelets: Low: \<100 G/L (AAR) and 20% DFB and High: \>=700 G/L (ad and ped).

  Baseline (Day 1 of original study) up to 9 years or until olipudase alfa was commercially accessible, whichever came first

• Number of Participants With PCSA in Electrocardiogram (ECG)

  PCSA: Heart rate: High:\>=120 bpm (ad, ado, chi), \>=140 bpm (ec), \>=175 bpm (inf) \& IFB\>=20 bpm for AAR, Heart rate: Low: \<=50 bpm (ad, ado, chi), \<=75 bpm (ec), \<=80 bpm (inf) \& DFB \>=20 bpm for AAR. PR duration: High: \>=200 milliseconds (ms) (ad) and IFB\>=20 ms, \>180 ms (ado), 170 ms (chi), 160 ms (ec), and 140 ms (inf). QT correction-Bazett (QTcB): Borderline absolute (category 1): 431-450 ms (ad and ado M, chi, ec and inf), 451-470 ms (ad and ado F), Prolonged-absolute (category 2): \>450 ms (ad and ado M and chi, ec and inf), \>470 ms (ad and ado F), Additional-absolute (category 3): \>=500 ms (AAR), Borderline increase (category 4): 30-60 ms (AAR), Prolonged increase (category 5): \> 60 ms (AAR).

  Baseline (Day 1 of original study) up to 9 years or until olipudase alfa was commercially accessible, whichever came first

• For Adults: Percent Change From Baseline in Pre-Infusion Plasma Ceramide at Month 90

  Plasma samples were collected to evaluate ceramide levels for safety biomarker analysis. Baseline was defined as the last available non-missing value prior to the first infusion in original study.

  Baseline (Day 1 of original study) and Month 90 (pre-infusion)

• For Pediatrics: Percent Change From Baseline in Pre-Infusion Plasma Ceramide at Month 66

  Plasma samples were collected to evaluate ceramide levels for safety biomarker analysis. Baseline was defined as the last available non-missing value prior to the first infusion in original study.

  Baseline (Day 1 of original study) and Month 66 (pre-infusion)

• Participants From Adult Study DFI13412: Number of Participants With Abnormal Liver Biopsy

  Liver biopsy samples were evaluated for sphingomyelin accumulation and liver pathology in the participants who previously participated in the DFI13412 study who were at least 18 years old when they entered in this study. Sphingomyelin accumulation was quantified in liver by computer morphometry of high-resolution light microscopy images. Fibrosis grading was assessed on the Laennec scoring system, which grades the extent of fibrosis on a scale from 0 to 4 (0=none; 1=minimal; 2=mild; 3=moderate; 4=cirrhosis). Higher score indicated more severity.

  Baseline (Day 1 of original study) and Month 36

• Participants From Pediatric Study DFI13803: Number of Participants With Abnormalities in Liver Ultrasound Doppler

  Liver ultrasound doppler was performed for pediatric participants transitioning from DFI13803 to document hepatic blood flow characteristics, principally portal vein pressure, and blood flow direction. The parameters evaluated were liver dysmorphic findings, liver surface abnormalities, mild ascites and hepatic steatosis. Liver ultrasound Doppler was performed using methods that were compatible with the standard institutional procedures of the investigational site.

  Baseline (Day 1 of original study), Week 2 and Months 12, 18 and 24

• Number of Participants With Anti-Drug Antibodies (ADA) Against Olipudase Alfa

  Blood samples were collected for the presence of ADAs against olipudase alfa. Treatment-boosted ADA: Positive ADA status positive at baseline (pre-existing ADA) and ADA titer level anytime post-baseline significantly higher than that at baseline. Transient ADA: Treatment-induced ADA detected only at 1 sampling time point post-baseline and treatment-induced ADA detected at 2 or more sampling time points post-baseline, where first and last ADA-positive samples (irrespective of any negative samples in between) separated by period of less than 16 weeks, and participant's last sampling time point was ADA-negative. Persistent ADA response: Treatment-induced ADA detected at 2 or more sampling time points post-baseline, where first and the last ADA-positive on-treatment sample (irrespective of any negative samples in between) separated by at least 16 weeks. Treatment-induced: ADA detected in the last 2 sampling time points, irrespective of the time period in between.

  Baseline (Day 1 of original study) up to 9 years or until olipudase alfa was commercially accessible, whichever came first

Secondary Outcomes (11)

• Percent Change From Baseline in Spleen and Liver Volumes at Month 102 for Adults and Month 84 for Pediatrics

  Baseline (Day 1 of original study), Month 102 for adults and Month 84 for pediatrics

• Change From Baseline in Pulmonary Imaging by High Resolution Computed Tomography (HRCT) at Month 102 for Adults and Month 84 for Pediatrics

  Baseline (Day 1 of original study), Month 102 for adults and Month 84 for pediatrics

• Percent Change From Baseline in Percent Predicted Diffusing Capacity of Lungs For Carbon Monoxide (DLco) (Hemoglobin-Adjusted) at Month 78 for Adults and Month 84 for Pediatrics

  Baseline (Day 1 of original study), Month 78 for adults and Month 84 for pediatrics

• Percent Change From Baseline in Platelet Count at Month 90 for Adults and Month 78 for Pediatrics

  Baseline (Day 1 of original study), Month 90 for adults (pre-infusion) and Month 78 for pediatrics (pre-infusion)

• Percent Change From Baseline in Low-density Lipoprotein at Month 90 for Adults and Month 66 for Pediatrics

  Baseline (Day 1 of original study), Month 90 for adults and Month 66 for pediatrics

Study Arms (1)

GZ402665

EXPERIMENTAL

GZ402665 administered intravenously once every 2 weeks at the dose each participant was receiving at the end of their previous olipudase alfa study, for 9 years or until olipudase alfa becomes commercially accessible, whichever comes first, unless the participant decides to enter another olipudase alfa clinical trial within the 9-year period prior to when olipudase alfa is commercially accessible.

Drug: GZ402665

Interventions

GZ402665 DRUG

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

Also known as: Olipudase alfa

GZ402665

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• The participant completed the treatment period of a previous study of olipudase alfa with an acceptable safety profile in the opinion of the investigator and sponsor.
• The participant and/or the participant's parent(s)/legal guardian(s) was willing and able to provide signed written informed consent.
• The participant who is female and of childbearing potential must have had a negative urine pregnancy test for beta human chorionic gonadotropin (β HCG).
• Female participants of childbearing potential and sexually mature male participants must have been willing to practice true abstinence in line with their preferred and usual lifestyle or use 2 acceptable effective methods of contraception up to 15 days following their last dose of study drug.

You may not qualify if:

• The participant had any new condition or worsening of an existing condition which in the opinion of the investigator would make the participant unsuitable for enrollment, or could interfere with the participation or completion the study.
• The participant, in the opinion of the investigator, was unable to adhere to the requirements of the study.
• The participant was unwilling or unable to abstain from the use of alcohol for 1 day prior to and 3 days after each olipudase alfa infusion for the duration of the treatment period.
• The participant was unwilling or unable to avoid, for 10 days before and 3 days after liver biopsies, medications or herbal supplements that are potentially hepatotoxic (only participants who previously participated in the DFI13412 study).
• The participant required medication(s) that may decrease olipudase alfa activity (eg, fluoxetine, chlorpromazine; tricyclic antidepressants \[eg, imipramine, desipramine\]).
• The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (9)

Investigational Site Number 840001

New York, New York, 10029-6574, United States

Location

Investigational Site Number 056001

Leuven, 3000, Belgium

Location

Investigational Site Number 076001

Porto Alegre, 90035 003, Brazil

Location

Investigational Site Number 250002

Bron, 69677, France

Location

Investigational Site Number 276002

Hochheim am Main, 65239, Germany

Location

Investigational Site Number 380002

Sassari, 07100, Italy

Location

Investigational Site Number 380001

Udine, 33100, Italy

Location

Investigational Site Number 826001

London, WC1N 3JZ, United Kingdom

Location

Investigational Site Number 826002

Manchester, M13 9WL, United Kingdom

Location

Related Publications (3)

• Scarpa M, Diaz GA, Giugliani R, Jones SA, Mengel E, Guffon N, Witters P, Ganesh J, Armstrong NM, Srivastava S, Kim Y. Long-Term Safety and Clinical Outcomes With Olipudase Alfa Enzyme Replacement Therapy in Children and Adolescents With Acid Sphingomyelinase Deficiency. J Inherit Metab Dis. 2025 Sep;48(5):e70086. doi: 10.1002/jimd.70086.

  PMID: 40937531 DERIVED

• Thurberg BL, Diaz GA, Lachmann RH, Schiano T, Wasserstein MP, Ji AJ, Zaher A, Peterschmitt MJ. Long-term efficacy of olipudase alfa in adults with acid sphingomyelinase deficiency (ASMD): Further clearance of hepatic sphingomyelin is associated with additional improvements in pro- and anti-atherogenic lipid profiles after 42 months of treatment. Mol Genet Metab. 2020 Sep-Oct;131(1-2):245-252. doi: 10.1016/j.ymgme.2020.06.010. Epub 2020 Jun 24.

  PMID: 32620536 DERIVED

• Wasserstein MP, Diaz GA, Lachmann RH, Jouvin MH, Nandy I, Ji AJ, Puga AC. Olipudase alfa for treatment of acid sphingomyelinase deficiency (ASMD): safety and efficacy in adults treated for 30 months. J Inherit Metab Dis. 2018 Sep;41(5):829-838. doi: 10.1007/s10545-017-0123-6. Epub 2018 Jan 5.

  PMID: 29305734 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 aventis recherche & développement

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 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: November 26, 2013
• First Posted: December 9, 2013
• Study Start: December 4, 2013
• Primary Completion: September 6, 2023
• Study Completion: September 6, 2023
• Last Updated: July 3, 2024
• Results First Posted: July 3, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share

Locations

DE (1); US (1); BR (1); FR (1); GB (2); IT (2); BE (1)