See “Lessons Learned From the Long-Term Use of Enzyme Replacement Therapy in the Treatment of Lysosomal Acid Lipase Deficiency” by Strong and Ficicioglu on page 726.
What Is Known/What Is New
What Is Known
- Lysosomal acid lipase deficiency is a rare lysosomal storage disorder with a diverse clinical spectrum.
- Sebelipase alfa, a recombinant human lysosomal acid lipase approved for lysosomal acid lipase deficiency, reduces serum aminotransferases and other markers of liver cell injury and improves lysosomal acid lipase deficiency-related dyslipidemia; in infants, patients with the most rapidly progressive form of the disease, sebelipase alfa prolongs survival.
What Is New
- This study expands the clinical experience with sebelipase alfa to include younger children and patients with previous hematopoietic stem cell or liver transplantation, advanced liver disease, or less common disease manifestations.
- On the basis of a small number of subjects with broad inclusion criteria completing 96 weeks of treatment, sebelipase alfa appears to improve or stabilize liver histopathology in most, but not all, patients.
- Further research is necessary to determine the extent to which sebelipase alfa improves liver histology, the role of concomitant dietary measures, and whether certain groups of patients benefit more from this treatment than others.
Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive lysosomal storage disease caused by biallelic pathogenic LIPA variants. Accumulation of cholesteryl esters and triglycerides in hepatocytes and macrophages leads to diverse clinical manifestations, including hepatomegaly, splenomegaly, liver injury, and dyslipidemia (1–3). Infantile disease is additionally characterized by malabsorption, diarrhea, failure to thrive, and adrenal calcifications (3). LAL-D can remain undetected (1,2,4) because of lack of awareness or misdiagnosis (1,2,5).
Low-fat diets and lipid-modifying medications minimally affect disease progression and do not prolong survival in infantile disease (1,2,4). Sebelipase alfa (KANUMA, Alexion, AstraZeneca Rare Disease, Boston, MA), a recombinant human LAL approved in the United States, European Union, and Canada (6–8), improves survival, growth, and liver function and is unequivocally lifesaving in infants with rapidly progressive LAL-D, and reduces signs of liver disease and abnormal lipid metabolism in children and adults with LAL-D (9–14). We report long-term efficacy and safety of sebelipase alfa in children and adults with LAL-D, including patients who may have been excluded from previous clinical studies because of more stringent inclusion criteria.
This 144-week, open-label, single-arm study (NCT02112994) was conducted at 19 sites in Australia, Europe, North America, and South America in accordance with Good Clinical Practice standards, including International Council for Harmonisation guidelines. All patients or legal representatives provided written informed consent. The protocol and amendments were approved by institutional review boards/independent ethics committees.
Eligible patients were >8 months old with confirmed LAL-D and ≥1 clinical manifestation: in patients <4 years old, dyslipidemia, elevated aminotransferases, impaired growth, suspected malabsorption, or other clinical manifestation; in patients ≥4 years old, advanced liver disease (cirrhosis with portal hypertension or esophageal varices), histologically confirmed recurrence (after previous liver transplant [LT] or hematopoietic stem cell transplant [HSCT], if any), persistent dyslipidemia, suspected malabsorption, or other clinical manifestation. Full eligibility criteria are provided in Text, Supplemental Digital Content 1, https://links.lww.com/MPG/C769.
The study included a screening period (≤45 days), treatment period (52–96 weeks), expanded treatment period (≤48 weeks), and follow-up telephone call to assess treatment-emergent adverse events (TEAEs) (≥4 weeks after last dose). All patients received intravenous sebelipase alfa 1.0 mg/kg every other week (qow), with possible escalation to 3.0 mg/kg qow and 3.0 mg/kg weekly (qw) per investigator discretion for disease progression (abnormal alanine aminotransferase [ALT], aspartate aminotransferase [AST], low-density lipoprotein cholesterol [LDL-C], or triglyceride levels that did not improve after 8 consecutive infusions; or, for children, a weight-for-age (WFA) z score 2 standard deviations below the mean for the past 6 months, assuming ≥80% treatment adherence. Significant liver disease progression was defined as confirmed ALT or AST levels >5 times the upper limit of normal (×ULN) and at least twice the highest pretreatment value, and 1 of the following: total bilirubin >3× ULN and at least twice the highest pretreatment value; prolonged prothrombin time ≥4 seconds above baseline; development/worsening of ascites; encephalopathy. Dose reduction for poor tolerability was per investigator discretion; the lowest dose allowed was 0.35 mg/kg qow. Reduction to 3.0 mg/kg qow was considered for patients with clinical improvement and ALT, AST, and LDL-C stability while receiving 3.0 mg/kg qw for ≥24 weeks.
Efficacy measures included changes from baseline to weeks 48, 96, and 144 in ALT, AST, LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglyceride, and total cholesterol levels; Child-Pugh score; UK-Model for End-Stage Liver Disease score; liver histopathology; and liver and spleen volume and fat content by magnetic resonance imaging. Additional measures included changes from baseline in gamma glutamyltransferase, alkaline phosphatase, bilirubin, albumin, and hemoglobin levels, platelet count, prothrombin time, international normalized ratio (INR), and macrophage activation markers (ferritin, high-sensitivity C-reactive protein). Liver and lipid panels were obtained every 4 weeks until week 12 and every 12 weeks thereafter; hematology and macrophage activation markers were assessed and coagulation panels obtained every 12 weeks. Blood samples were assessed by a central laboratory. Adults fasted for ≥9 hours and abstained from alcohol for 24 hours before sample collection.
Liver biopsies were obtained at screening and week 48 (±2 weeks); week 96 biopsies were optional. A biopsy obtained <26 weeks before screening could replace a screening biopsy. Biopsies were evaluated semiquantitatively at a central facility by an independent pathologist blinded to assessment timepoint. Ishak stage, steatosis scores, and lobular and portal inflammation scores were assigned as described in Text, Supplemental Digital Content 2, https://links.lww.com/MPG/C769.
For children, WFA and height-for-age (HFA) percentiles were determined using standard growth charts (15,16). Health-related quality of life (QOL), an exploratory outcome, was measured with the Functional Assessment of Chronic Illness Therapy-Fatigue and Chronic Liver Disease Questionnaire in patients ≥17 years of age and with the Pediatric Quality of Life questionnaire in patients 5 to <18 years of age at the time of informed consent.
Safety outcomes included TEAEs (occurring on or after drug administration day 1, or present earlier and worsening in frequency or severity during treatment), serious TEAEs (SAEs), infusion-associated reactions (IARs), and anti-drug antibody analyses. TEAEs were coded by system organ class and preferred term using the Medical Dictionary for Regulatory Activities version 19.1. Vital signs, physical examinations, clinical laboratory test results, and 12-lead electrocardiograms (ECGs) were assessed, and concomitant medications were recorded. The Denver II developmental screening test (17) assessed development in patients ≤6 years old.
Given the rarity of LAL-D, planned enrollment, based on feasibility, was approximately 30 patients. No formal sample size calculations were performed.
Efficacy and safety were assessed in the full analysis set (patients who received ≥1 sebelipase alfa infusion). Clinical laboratory data were summarized as continuous variables; select efficacy data were summarized relative to laboratory normal ranges. Liver and spleen volume and fat content were evaluated by multiples of normal (MN; normal = 2.5% of body weight [liver], 0.2% of body weight [spleen]) and percentage, respectively, and summarized as continuous variables. Median change from baseline is reported for patients with paired baseline and follow-up data. Continuous data were summarized using descriptive statistics, categorical data as number and percentage. Missing data were not imputed. No inferential statistical analyses were conducted. All analyses were performed with SAS statistical software version 9.2 or higher.
Of 38 patients screened, 31 (22 children, 9 adults) received sebelipase alfa, 4 were deemed ineligible, and 3 withdrew consent. The first patient enrolled on June 24, 2014 and the last completed the study on December 28, 2017. Twenty-eight patients (90%) completed 96 weeks, and 19 completed 144 weeks. Three patients did not complete the 96-week treatment period because of transition to commercial product (n = 1, week 76), pregnancy (n = 1, week 64), and withdrawal of consent (n = 1, week 61). Three did not continue into the 48-week extended treatment period because of pregnancy (n = 1), disease progression (n = 1), and transition to commercial product (n = 1). Of the 25 patients who entered the extended treatment period, 6 did not complete 144 weeks because of transition to commercial product (n = 4), withdrawal of consent (n = 1, week 140), and LT (n = 1, week 136). Only 2 patients who entered the extended treatment period discontinued treatment.
Patients meeting key inclusion criteria are summarized in Table S1, Supplemental Digital Content 3, https://links.lww.com/MPG/C769. At baseline, median age was 12 (range, 3–55) years, 61% were boys, and 52% were taking lipid-modifying medication (Table S2, Supplemental Digital Content 4, https://links.lww.com/MPG/C769). Of 30 patients with evaluable biopsies, 20 had fibrosis, 8 had cirrhosis, and 2 had neither (1 <4 years old, 1 prior LT). Twenty-eight (90%) patients were receiving at least 1 medication at baseline. All 31 received ≥1 concomitant medication during the study; 17 (55%) received lipid-modifying medication.
Children represented >70% of the study population, and no specific clinical profile distinguished children from adults; thus, results reported for the entire study population reflect results in children. Marked improvements in liver and lipid parameters were observed and maintained during treatment (Tables 1 and 2; Figure S1, Supplemental Digital Content 5, https://links.lww.com/MPG/C769). At week 144, 84% and 95% of patients had ALT and AST levels ≤1.5×ULN, respectively, versus 42% and 52% at baseline. Prothrombin time and INR remained stable throughout the study.
TABLE 1 -
Change in liver biomarkers from baseline to week 144
||Absolute value (change from baseline)
||Baseline, N = 31
||Week 48, N = 29
||Week 96, N = 27
||Week 144, N = 19
||36.0 (15–117)[−21.5 (−147 to 25)]
||34.0 (17–75)[−29.0 (−136 to 49)]
||38.0 (20–78)[−42.0 (−163 to 52)]
||42.0 (13–91)∗[−17.5 (−227 to 52)]∗
||42.0 (15–64)[−15.0 (−223 to 18)]
||41.0 (22–71)[−22.0 (−245 to 32)]
||19.0 (9–84)[−9.0 (−138 to 26)]
||17.0 (9–221)[−7.5 (−149 to 162)]
||16.0 (9–90)[−10.0 (−166 to 25)]
||41.0 (24–47)[−0.5 (−9 to 7)]
||41.0 (24–52)[−1.7 (−4 to 10)]
||42.0 (28–48)[−1.0 (−6 to 6)]
||135.0 (101–150)∗[2.0 (−27 to 46)]‡
||133.0 (112–153)§[1.0 (−11 to 12)]¶
||135.0 (116–152)#[3.0 (−10 to 11)]#
|Platelet count, × 109/L
||240.5 (20–482)∗[−7.0 (−125 to 162)]‡
||226.0 (22–407)§[3.0 (−102 to 71)]¶
||253.0 (55–425)#[17.0 (−73 to 70)]#
|Prothrombin time, seconds
||12.1 (8.5–19.0)¶[0.04 (−5.0 to 1.1)]∗∗
||12.1 (8.3–17.7)††[0.0 (−4.3 to 0.8)]††
||12.3 (7.9–17.7)#[−0.7 (−1.8 to 0.5)]‡‡
||1.0 (0.9–1.4)[–0.02 (–0.4 to 0.1)]
||1.0 (0.9–1.4)¶[–0.01 (–0.3 to 0.04)]¶
||1.1 (0.9–1.3)§§[–0.04 (–0.2 to 0.04)]§§
|Serum ferritin, μg/L
||38.2 (10.0–201.6)‡[−6.5 (−101.1 to 44.5)]‡
||34.0 (12.9–194.5)[−9.0 (−113.9 to 48.9)]
||33.5 (12.9–318.2)§§[0.4 (−39.6 to 121.8)]§§
||1.2 (0.2–43.1)[−0.5 (−24.0 to 42.5)]
||0.8 (0.2–7.9)[−0.3 (−22.9 to 7.1)]
||0.7 (0.2–8.0)[−0.1 (−11.2 to 3.9)]
|Total bilirubin, μmol/L
||8.0 (3–70)[−0.5 (−21 to 23)]
||10.0 (3–60)[0.0 (−31 to 16)]
||7.0 (3–70)[−1.0 (−21 to 8)]
|Alkaline phosphatase, U/L
||244.0 (41–670)[−13.5 (−216 to 137)]
||232.0 (37–615)[−15.3 (−236 to 82)]
||287.0 (72–588)[−31.0 (−175 to 55)]
||5.0 (5–7)¶¶[0.0 (−4 to 1)]¶¶
||5.0 (5–9)¶¶[0.0 (−4 to 4)]¶¶
||5.0 (5–8)§§[0.0 (0 to 1)]§§
||46.1 (40–53)††[−0.3 (−4 to 6)]#
||45.5 (42–51)¶¶[−0.3 (−3 to 3)]#
||44.4 (40–53)#[−1.4 (−5 to 2)]##
Median changes from baseline values are reported for only those patients who had data at both baseline and week 48, 96, or 144. For comparative purposes, ULNs used by the central laboratory for ALT were: girls (any age) and boys <10 years of age: 34 U/L; boys ≥10 years: 43 U/L. ULNs for AST were: ≥18 years of age: girls, 34 U/L; boys, 36 U/L; 7 to <18 years: girls and boys, 40 U/L; 4 to <7 years: girls, 48 U/L; boys, 59 U/L; <4 years: girls, 56 U/L; boys, 69 U/L. ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma glutamyltransferase; hs-CRP = high sensitivity C-reactive protein; INR = international normalized ratio; UK-MELD = United Kingdom Model for End-Stage Liver Disease; ULN = upper limit of normal.
∗n = 28.
†n = 30.
‡n = 27.
§n = 26.
¶n = 25.
#n = 17.
∗∗n = 24.
††n = 21.
‡‡n = 16.
§§n = 18.
¶¶n = 22.
##n = 15.
TABLE 2 -
Change in lipid biomarkers from baseline to week 144
||Absolute value (change from baseline)
||Baseline, N = 31
||Week 48, N = 29
||Week 96, N = 27
||Week 144, N = 19
||122.4 (41–241)†−39.1 (−125 to 50)‡
||133.0 (40–277)§[−45.2 (−117 to 142)]§
||121.0 (42–176)[−52.6 (−112 to 32)]
||36.3 (13–68)[5.2 (−8 to 38)]
||37.1 (24–58)[7.9 (−10 to 27)]
||38.3 (15–56)[9.8 (−2 to 32)]
||160.9 (51–255)[−42.9 (−139 to 33)]
||158.2 (52–292)[−51.0 (−133 to 136)]
||149.7 (58–203)[−64.0 (−130 to 30)]
||106.3 (43–421)[−34.5 (−171 to 96)]
||90.3 (37–570)[−41.6 (−173 to 246)]
||111.6 (53–268)[−35.4 (−172 to 127)]
|Total cholesterol, mg/dL
||184.8 (87–284)[−35.4 (−134 to 35)]
||196.1 (84–329)[−48.5 (−127 to 137)]
||192.6 (93–238)[−54.7 (−118 to 45)]
Median changes from baseline values are reported for only those patients who had data at both baseline and weeks 48, 96, or 144. HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; LLN = lower limit of normal; ULN = upper limit of normal. The generally accepted ULN for LDL-C is 129 mg/dL in children and adults; the generally accepted LLN for HDL-C is 40 mg/dL in children and adult males and 50 mg/dL in adult females (20)
.HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; LLN = lower limit of normal; ULN = upper limit of normal.
∗n = 30.
†n = 28.
‡n = 27.
§n = 25.
Median LDL-C level decreased from baseline, and median HDL-C level increased from baseline after 144 weeks (Table 2; Figure S2, Supplemental Digital Content 6, https://links.lww.com/MPG/C769). Among patients receiving lipid-modifying medications at baseline, 1 receiving atorvastatin had dose reductions at weeks 38 and 74. One patient initiated atorvastatin at week 26, with a dose reduction at week 60.
Median liver volume, spleen volume, and liver fat content decreased from baseline, and median spleen fat content increased from baseline, at week 144 (Table 3).
TABLE 3 -
Change in liver and spleen imaging from baseline to week 144
||Absolute value (change from baseline)
||Baseline, N = 31
||Week 48, N = 29
||Week 96, N = 27
||Week 144, N = 19
|Liver volume, MN
||1.3 (0.6–2.3)†[−0.2 (−0.5 to 0.2)]‡
||1.2 (0.7–1.8)§[−0.3 (−0.7 to −0.03)]||
||1.3 (1.0–1.7)¶[−0.3 (−1.0 to −0.1)]#
|Liver fat content, %
||8.1 (−1.0 to 14.8)∗∗
||6.2 (0.5–16.1)†[−1.2 (−6.6 to 7.1)]†
||6.5 (0.1–20.5)§[−1.1 (−9.1 to 11.4)]§
||8.1 (−1.0 to 16.3)¶[−0.5 (−5.6 to 4.5)]#
|Spleen volume, MN
||2.7 (1.0–19.2)†[−0.2 (−5.4 to 0.8)‡
||2.2 (1.1–20.8)††[−0.4 (−5.6 to 0.2)]||
||2.3 (1.3–3.9)#[−0.4 (−2.8 to 0.5)]#
|Spleen fat content, %
||1.3 (–0.8 to 8.7)∗
||1.8 (−0.8 to 8.1)§[0.1 (−2.2 to 2.5)]§
||1.6 (−0.5 to 4.4)††[0.0 (−5.0 to 4.1)]††
||1.7 (−0.4 to 3.3)#[0.3 (−1.5 to 1.9)]‡‡
Median changes from baseline values are reported for only those patients who had data at both baseline and week 48, 96, or 144. MN = multiples of normal (normal = 2.5% of body weight [liver], 0.2% of body weight [spleen]).
∗n = 27.
†n = 26.
‡n = 25.
§n = 24.
||n = 22.
¶n = 13.
#n = 12.
∗∗n = 28.
††n = 23.
‡‡n = 11.
Changes in Ishak stage among 27 patients with paired Ishak stage data at baseline and week 48 and among 16 patients with paired Ishak stage data at baseline and week 96 are shown in Figure 1A. Of 20 patients with baseline stage 0 to 5, 15 (75%) improved or had not progressed at week 48. Of 7 patients with baseline stage 6, 1 improved to stage 3 and 1 improved to stage 4 at week 48. Of the 27 patients with paired data at baseline and week 48, 14 had biopsy data at week 96. Of the remaining 13, 2 showed increased fibrosis at week 48, 5 had no change (including 3 who remained stage 6), and 6 improved, suggesting that patients with liver biopsy at week 96 had less favorable outcomes at week 48 compared with those with no further biopsy. Among 13 patients with baseline stage 0 to 5, fibrosis improved or did not progress in 7 (54%) at week 96. Of 3 patients with baseline stage 6, 1 improved to stage 2 at week 96. The 4 patients with ≥2-stage reduction from baseline to week 48 and the 2 patients with ≥2-stage reduction from baseline to week 96 generally had robust improvements in ALT, liver fat content, and lipid parameters at the same timepoints. Median (range) percent steatosis was 11.8% (2.2%–43.5%) at baseline (n = 30). Median (range) absolute change from baseline was −3.8% (−13.1% to 27.1%) at week 48 (n = 28) and −1.8% (–13.5% to 12.4%) at week 96 (n = 16).
Five of 30 (17%) patients had macrovesicular steatosis and 28 (93%) had microvesicular steatosis at baseline. Most macrovesicular steatosis scores were unchanged at weeks 48 and 96 (Fig. 1B). Most patients (70%) had severe microvesicular steatosis at baseline (>66% hepatocyte involvement/replacement), which decreased to approximately 40% at weeks 48 and 96. Of the patients with improved microvesicular steatosis at week 48 (Fig. 1B), 9 had a ≥2-point reduction; of those with improved microvesicular steatosis at week 96, 4 had a ≥2-point reduction. These findings are consistent with reductions in morphometric steatosis analyses and reductions in liver fat content. Lobular and portal inflammation were present in 29 of 30 patients at baseline. Lobular inflammation scores were unchanged or worsened in most patients at weeks 48 and 96 (Fig. 1B); most patients with worsening had a 1-point increase in score (week 48: 10/14 [71%]; week 96: 5/6 [83%]). Portal inflammation scores were unchanged from baseline in most patients at weeks 48 and 96 (Fig. 1B).
Changes in liver and lipid parameters in the 8 patients with cirrhosis at baseline are summarized in Table S3, Supplemental Digital Content 7, https://links.lww.com/MPG/C769. Five patients with advanced liver disease demonstrated robust treatment responses (ALT and AST levels within or approaching normal range at last assessment), liver fat content was reduced in 4 with baseline and follow-up data, and liver volume was reduced in 3 with baseline and follow-up data. Although LDL-C, triglyceride, and total cholesterol levels were predominantly normal at baseline, they generally decreased and were normal or low throughout treatment; 3 patients had HDL-C increases. Changes in liver and lipid parameters for the 4 patients who had received prior LT or HSCT are described in Text, Supplemental Digital Content 8, https://links.lww.com/MPG/C769.
In children, WFA percentiles ranged from 0.40% to 99.60% (median, 18.4%) at baseline, and HFA percentiles ranged from 0.01% to 79.98% (median, 22.2%). Among children ages 2 to <4 years, median baseline WFA percentile was 27.8% and HFA percentile was 27.9%; corresponding values among children ages 4 to ≤18 years were 18.4% and 18.5%, respectively. For the 17 patients with follow-up data at week 144, the median WFA percentile was 25.96% (absolute median change from baseline, 0.75%). At week 144 or last assessment, 13 patients had improved WFA percentiles, with increases ranging from 0.01% to 40.27%, whereas 9 patients had worsening, with decreases ranging from −0.19% to −13.57%. The corresponding median HFA percentile was 19.67% (absolute median change from baseline, 0.57%). Eleven patients had improved HFA percentiles, with absolute increases ranging from 0.02% to 32.33%, whereas 6 patients had worsening, with absolute decreases ranging from −1.85% to −16.36%. No marked differences were noted in median effects by age.
Health-related QOL data showed considerable intersubject variability, and paired follow-up data were limited. No consistent treatment effect of sebelipase alfa was identified.
Mean sebelipase alfa exposure was 129.9 (range, 61–145; Q1–Q3, 136–144) weeks. Thirteen patients had dose escalations (11 [8 children] to 3.0 mg/kg qow) and 4 underwent additional escalation to 3.0 mg/kg qw (2/4 were 2 to ≤4 years old; 1 was 4 to ≤18 years old and underwent HSCT at ∼3 months of age; 1 adult who underwent HSCT at ∼8 months of age). The other 2 patients received 1 or 3 infusions of 1.0 mg/kg qw. One adult had a dose reduction to 0.35 mg/kg qow at week 26.
Sebelipase alfa was generally well tolerated. The most common TEAEs were pyrexia (55%), nasopharyngitis (45%), and diarrhea (42%) (Table S4, Supplemental Digital Content 9, https://links.lww.com/MPG/C769). Most TEAEs were mild to moderate (87%) and unrelated to treatment (68%). Ten (32%) patients experienced ≥1 treatment-related TEAE. Most common were general and administration-site conditions (5 [16%] patients), gastrointestinal disorders (4 [13%] patients), and skin and subcutaneous tissue disorders (4 [13%] patients). Ten patients (32%) reported ≥1 SAE; 1 experienced 2 treatment-related events of anaphylaxis; the patient underwent desensitization and remained in the study through week 96. An LT candidate at study entry who showed improved liver function test results and hepatic steatosis discontinued treatment because of an SAE (LT; unrelated to sebelipase alfa). No deaths occurred on study.
Other clinically significant adverse events were IARs in 3 (10%) patients (hypothermia and increased blood pressure in a 3-year-old; pyrexia, skin reaction, lip swelling, and urticaria in a 10-year-old; and anaphylactic reaction [2 episodes], urticaria, pruritic rash, and conjunctival hyperemia in a 45-year-old). IARs were mild (n = 1) or moderate (n = 2) in intensity. Anaphylactic reaction IARs were assessed as serious; all others were nonserious.
Two patients (6%) had positive antidrug antibody tests at a single timepoint (weeks 4 and 12); neither developed neutralizing antibodies.
Vital sign changes most frequently reported as TEAEs were body temperature elevations (pyrexia [55%], increased body temperature [10%], and hyperthermia [3%]). From baseline to week 144, proportions of patients with a palpable liver, palpable spleen, and tender spleen decreased from 77% to 42%, 32% to 16%, and 20% to zero, respectively. Baseline ECGs were normal for 23 (74%) patients and abnormal but not clinically significant for 8 (26%); at week 96, 1 ECG was abnormal and clinically significant, with evidence of a pre-study myocardial infarction and TEAEs of left ventricular dilatation and left ventricular cardiac hypertrophy, assessed as nonserious, moderate, unrelated to treatment, and ongoing at end of study. No clinically meaningful changes were observed in hematology, coagulation, or serum chemistry parameters.
Seven of 8 age-appropriate patients took the Denver II test at baseline. Of these, 6 tested “normal” and continued to test “normal” at week 96. One patient tested “suspect” at baseline and “normal” at week 96. All 5 patients with follow-up data at week 144 tested “normal.”
LAL-D is associated with significant morbidity and early mortality (4,18). Sebelipase alfa enzyme replacement therapy improves the prognosis for patients with LAL-D (9–14,19). This study shows that long-term sebelipase alfa treatment is generally well tolerated and improves liver and lipid parameters, with no apparent progression of liver disease, in most, but not all LAL-D patients of all ages, including individuals with prior HSCT or LT, advanced liver disease, or less common disease manifestations. No patient required LT, although 1 candidate with advanced liver disease at baseline who showed improvement in liver function, hepatic steatosis, and Child-Pugh score (10 [class C] at baseline and 5 [class A] at week 132) discontinued treatment for LT because of continued cirrhosis per an unscheduled liver biopsy at week 138.
These results are consistent with findings from the phase 3 registration study (ARISE; LAL-CL02) showing sebelipase alfa superiority to placebo in reducing ALT and AST levels and improving lipid abnormalities and liver fat content with good tolerability in children and adults with LAL-D (14) and benefits sustained for up to 5 years of therapy (19). In another long-term study, in adults (LAL-CL04), sebelipase alfa treatment for up to 5 years achieved sustained improvements in markers of liver and lipid dysfunction and liver volume and fat content and was well tolerated (13). Compared with ARISE and LAL-CL04, this study had broader inclusion criteria, resulting in a more heterogeneous patient population with more challenging stages of illness, including 4 patients who had received prior LT or HSCT that did not prevent liver disease recurrence. Some patients were younger than those in ARISE and LAL-CL04 and did not have evidence of advanced disease at enrollment.
The assessment of treatment response depends on the disease phenotype at baseline, the dose of sebelipase alfa, the dietary regimen employed, and concomitant diseases and medications. From findings in infants, we know that a dose increase and effective dietary care may be needed to achieve an effective response (10). Therefore, suspected nonresponders should be assessed for any underlying comorbidities that may be contributing to the severity and progression of disease before consideration of discontinuing sebelipase alfa.
Study limitations include the open-label, noncontrolled design, which did not allow for statistical comparisons, and small sample size, consistent with a rare disease study. No statistical comparisons between age groups were performed. As the architecture of liver tissue is not homogeneous, and fibrotic/cirrhotic tissue density may vary by liver region, Ishak staging may have been influenced by sampling location. The small number of patients with paired data and the limitations of subjective scoring also may have influenced biopsy results. More than half (55%) of the study population received concomitant lipid-modifying therapy; thus, the individual contributions of sebelipase alfa and lipid-modifying therapy cannot be determined. Dietary information was not collected systematically; 16 patients were 4 to ≤18 years old at the first infusion, and metabolic and dietary changes during puberty and adolescence might have affected outcomes. Inclusion of few children with growth impairment and lack of a consistent effect of sebelipase alfa on growth parameters in all children included in this study suggest a need to further evaluate factors influencing growth in children presenting with LAL-D-related growth impairment.
Despite these limitations, these data provide the first evidence demonstrating the benefit of sebelipase alfa in this broad population of patients with LAL-D.
These results confirm that sebelipase alfa treatment provides sustained improvements in measures of lipid and liver dysfunction and is generally safe and well tolerated in LAL-D patients for up to 144 weeks. Early treatment initiation may improve disease-relevant liver and lipid biomarkers and prevent potentially serious disease-related adverse outcomes. Further research is necessary to determine the impact of sebelipase alfa on QOL measures, the extent to which sebelipase alfa improves liver histology, the role of concomitant dietary measures, and whether certain groups of patients with LAL-D benefit more from sebelipase alfa than others.
We thank the patients and their families for their participation in this study. The authors are grateful for the contributions of all study investigators, the health care professionals who provided care for these patients, and Zachary Goodman, MD, PhD, of Inova Fairfax Hospital, Falls Church, Virginia, USA, the independent expert hepatopathologist for this study. The following institutions enrolled and/or treated patients in this study: Cliniques Universitaires Saint-Luc, Brussels, Belgium; Universidad de Federal de São Paulo, São Paulo, Brazil; Capital District Health Authority, Halifax, Nova Scotia, Canada; Clinic Hospital Center Zagreb, Zagreb, Croatia; Righospitalet Copenhagen University Hospital, Copenhagen, Denmark; University Hospital Freiburg, Freiburg, Germany; U.O.C. Malattie Metaboliche Ereditarie, Padova, Italy; Hospital Infantil de México Federico Gómez, Ciudad de Mexico, Mexico; Federal State Institution “Russian Children's Clinical Hospital,” Moscow, Russian Federation; Hospital Universitario La Paz, Madrid, Spain; Hospital Clinic i Provincial, Barcelona, Spain; Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain; Cukurova Universitesi Tip Fakultesi Balcali Hastanesi, Adana, Turkey; Birmingham Children's Hospital NIHR—Wellcome Trust Clinical Research Facility, Birmingham, UK; Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA; LSU Health Sciences Center—Shreveport, Shreveport, Louisiana, USA; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; The Children's Hospital at Westmead, Westmead NSW, Australia; Academic Medical Center, Emma Children's Hospital, Amsterdam, Netherlands. Editorial and medical writing support was provided by Jessica D. Herr, PharmD, of Peloton Advantage, LLC, Parsippany, NJ, an OPEN Health company, and was funded by Alexion, AstraZeneca Rare Disease.
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