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

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.

Time frame: Baseline (Day 1 of original study), Month 78

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

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

Time frame: Baseline (Day 1 of original study), Month 78

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

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.

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

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.

Time frame: Baseline (Day 1 of original study), Month 84

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

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.

Time frame: Baseline (Day 1 of original study), Month 84

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

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.

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

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.

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study.

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.

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study.

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).

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study.

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).

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study.

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).

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study.

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.

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study.

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.

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study.

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.

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study.

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.

Time frame: Baseline (Day 1 of original study) and Month 36

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study.

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.

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study.

Pulmonary imaging of chest using HRCT was obtained for qualitative assessment of ground glass appearance, interstitial lung disease, pleural thickening and reticulo-nodular density. Images were collected and read centrally by a third party blinded to participant number and study visit. Lung fields were scored subjectively for degree of diffuse lung disease (infiltrative lung disease) in scale of 0-3 ranging from 0 = No disease, 1 = Mild (affecting 1% to 25% of the lung volume), 2 = Moderate (affecting 26% to 50% of the lung volume), 3 = Severe (affecting 51% to 100% of the lung volume) where higher scores indicated more severity. The score of each participant was averaged over all 4 levels and both sides of lung. Mean score across 4 levels and both lungs = (Mean score across X levels for left lung + Mean score across X levels for right lung)/2. Baseline was defined as the last available non-missing value prior to the first infusion in original study.

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

The BFI involves a total of 9 items:3 of which measure BFI-fatigue severity score and 6 of which measure BFI-fatigue interference score. Score for each item measuring severity score is assessed by numerical rating scale (NRS); ranges from 0-10 from 0 (no fatigue) to 10 (worst imaginable fatigue) ultimately leading to overall severity score that ranges from 0-30. Respectively, amount that fatigue interfered with different aspects of participant's life during preceding 24 hours (general activity,mood,walking ability,normal work,relations with other people,and enjoyment of life) is captured as part of interference score.These different aspects are measured in scores ranging from 0:does not interfere and 10:completely interferes,ultimately leading to overall interference score ranging between 0-60. Higher scores in both categories mentioned below indicate worse outcome; mean is presented. Baseline was defined as last available non-missing value prior to first infusion in original study.

Time frame: Baseline (Day 1 of original study) and Month 78

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints for each specified category are reported.

The BPI-SF is a 15-item, validated, self-administered questionnaire designed to measure participant's perceived level of pain. The BPI-SF measured the participant's intensity of pain (sensory dimension), the interference of pain in participant's life (reactive dimension), and asked participant about pain relief, pain quality, and perception of cause of pain. Scoring was based on 4 out of 8 questions in pain severity domain, and 7 questions in pain interference domain, which used numerical rating scale. Pain severity response ranged from 0 = No pain to 10 = Pain as bad as you can imagine. Pain interference response ranged from 0 = Does not interfere to 10 = Completely interferes. Scores were averaged and mean is presented here. Higher scores indicated greater intensity of pain. Baseline was defined as the last available non-missing value prior to the first infusion in original study.

Time frame: Baseline (Day 1 of original study) and Month 78

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study.

The CRQ-SAS is a validated, self-administered questionnaire designed to evaluate health related quality of life (HRQoL) in adults with chronic airflow limitation, chronic respiratory disease and cystic fibrosis. It had 20 items and evaluated 4 dimensions of respiratory impairment (dyspnea, emotional function, fatigue and participant's feeling of control over the disease \[mastery\]). Each domain was measured on 7-point-scale, with 8 reserved for not done (1: worst and 7: best). Each domain score was calculated separately. Scores for each question of each domain were added together and divided by number of questions answered in each domain. Only items answered were scored. Mean of average score of completed items is reported. Higher scores indicated better HRQoL in each domain. Baseline was defined as last available non-missing value prior to first infusion in original study.

Time frame: Baseline (Day 1 of original study) and Month 78

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study.

Hand X-ray was performed on participant's left hand, fingers and wrist to assess the bone age. The X-rays were collected and read centrally by a third party blinded to participant number and study visit. At each visit, 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. Baseline was defined as the last available non-missing value prior to the first infusion in original study.

Time frame: Baseline (Day 1 of original study) and Month 72

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

Linear growth in pediatric participants was assessed by height Z-scores. 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 indicated an improvement on growth. Baseline was defined as the last available non-missing value prior to the first infusion in original study.

Time frame: Baseline (Day 1 of original study) and Month 72

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

PedsQL included a child self-report for participants 5 to 18 years and parents' report of participants from 2 to 18 years. Child-reported: 23-item PedsQL Generic Core Scales report included 4 scales, physical functioning, emotional functioning, social functioning, and school functioning. Parent-reported: 21-item PedsQL Generic Core Scales report and included similar scales as above. 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. All summary/total scores were mean of specific items where higher score indicated better HRQoL. Baseline was defined as the last available non-missing value prior to the first infusion in original study.

Time frame: Baseline (Day 1 of original study) and Month 72

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

Blood samples were collected at specified timepoints for fasting lipids as ASMD leads to progressive accumulation of lipids. Baseline was defined as the last available non-missing value prior to the first infusion in original study.

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

DLco was used to measure gas exchange across the alveolocapillary membrane. Percent predicted hemoglobin-adjusted DLco was calculated as: 100 x Adjusted DLco/Predicted DLco in unit of mL co/minute (min)/mmHg where, adjusted DLco = Observed DLco (in mL co/min/mmHg) divided by Hemoglobin-adjusted factor. Baseline was defined as the last available non-missing value prior to the first infusion in original study.

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

Blood samples were collected at specified timepoints for the estimation of platelet count as ASMD is known to result in hematologic disorders. Baseline was defined as the average of all available values before the start of first infusion from original study

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.

Spleen and liver volumes were assessed by abdominal magnetic resonance imaging (MRI) collected and read centrally by a third party blinded to participant number and study visit to quantify the degree of splenomegaly and hepatomegaly at specified time points. Spleen/Liver volume in multiples of normal (MN) = Spleen/Liver volume (cubic centimeter \[cm\^3\]) / \[2xweight (kg)\] where weight was the available value closest to the MRI scan date. Negative value signifies reduction of volume. Baseline was defined as the last available non-missing value prior to the first infusion in original study.

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

Population: Results are based on the Safety analysis set which consisted of all enrolled participants who received at least 1 infusion (partial or total) of olipudase alfa in the current study. Only those participants with data collected at specified timepoints are reported.