Patients
The VITAL study enrolled patients from May 2011 through December 2013 at 8 sites in 6 countries (United Kingdom [UK], United States [US], France, Ireland, Egypt, and Turkey). The CL08 study enrolled patients from June 2014 to May 2016 at 5 sites in 4 countries (US, Finland, and UK; 1 patient who initiated treatment in the UK subsequently transferred to a site in Italy to receive treatment). Nineteen patients were enrolled (10 males, 9 females) and received treatment in the 2 studies (VITAL, n = 9; CL08, n = 10); 13 patients completed the studies or switched to the commercial product upon study termination (CL08 only) (VITAL, n = 5; CL08, n = 8). Six patients died during the studies (4 in VITAL and 2 in CL08); none of the deaths was considered to be related to sebelipase alfa treatment. Baseline demographic and disease characteristics of the treated patients are summarized in Table 1. The CL08 population appeared to have more severe disease at baseline, based on lower World Health Organization (WHO) percentiles for weight-for-age and mid-upper arm circumference-for-age.
Table 1
Baseline Patient Demographic and Disease Characteristics (Full Analysis Set)
Parameter
|
VITAL
(N = 9)
|
CL08
(N = 10)
|
Age at first dose, months, median (range)
|
3.0 (1–6)
|
2.8 (0.5–4)
|
Sex, n (%)
|
|
|
Male
|
5 (56)
|
5 (50)
|
Female
|
4 (44)
|
5 (50)
|
Race, n (%)
|
|
|
American Indian or Alaska Native
|
0
|
1 (10)
|
Asian
|
1 (11)
|
6 (60)
|
Black
|
1 (11)
|
0
|
White
|
4 (44)
|
1 (10)
|
Other
|
0
|
2 (20)
|
Unknown
|
3 (33)
|
0
|
Anthropometric parameters, median (IQR)
|
|
|
Weight-for-age, WHO percentilea
|
3.1 (1–8)b
|
1.1 (0.0–8)
|
Length (height)-for-age, WHO percentilea
|
1.8 (0.1–39)b
|
2.9 (0.6–50)c
|
Mid-upper arm circumference-for-age, WHO percentilea
|
0.01 (0.0–0.3)d
|
0.001 (0.0–0.3)e
|
Liver parameters, median (range)
|
|
|
ALT
|
|
|
U/L
|
145.0 (16–297)
|
37.0 (28–248)c
|
µkat/L
|
2.42 (0.3–5.0)
|
0.62 (0.5–4.1)c
|
AST
|
|
|
U/L
|
125.0 (71–716)
|
99.5 (56–441)b
|
µkat/L
|
2.09 (1.2–12.0)
|
1.66 (0.9–7.4)b
|
Ferritin
|
|
|
µg/L (ng/mL)
|
586.3 (253–48,740)f
|
1750.5 (481–3020)g
|
Albumin, g/L
|
29.0 (13–40)
|
20.0 (18–29)c
|
Total bilirubin
|
|
|
mg/dL
|
1.7 (0.2–27)
|
0.7 (0.2–3)
|
µmol/L
|
29.0 (3–464)b
|
12.0 (4–52)c
|
Hematologic parameters, median (range)
|
|
|
Hemoglobin, g/L
|
93.0 (1–103)
|
90.0 (81–131)f
|
Platelets, 109/L
|
173.0 (3–563)
|
146.0 (56–235)f
|
LAL-D manifestations, n (%)
|
|
|
Hepatomegaly and/or splenomegaly
|
9 (100)
|
9 (90)
|
Diarrhea and/or vomiting
|
9 (100)
|
9 (90)
|
Adrenal calcification
|
9 (100)
|
5 (50)
|
Failure to thrive/malnutrition
|
9 (100)
|
5 (50)
|
Liver volume, MN, median (range)
|
3.4 (3–4)h
|
3.2 (0.1–4)f
|
Spleen volume, MN, median (range)
|
7.0 (3–10)g
|
5.8 (0.7–15)b
|
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CDC, Centers for Disease Control and Prevention; IQR, interquartile range; LALD, lysosomal acid lipase deficiency; MN, multiples of normal; WHO, World Health Organization. |
a Based on WHO Multicenter Growth Reference Study Group, 2006 and 2007 WHO Child Growth Standards [18, 19]. After age 2, standardization is based on 2000 CDC Growth Chart [20]}. |
b n = 8. |
c n = 9. |
d n = 4. |
e n = 5. |
f n = 7. |
g n = 2. |
h n = 3. |
Efficacy
Survival
Patient survival in each study is shown in Fig. 1. The median (range) age of surviving patients at end of study was 5.2 (4.8–5.6) years in VITAL and 3.2 (2.3–3.4) years in CL08. In VITAL, the Kaplan-Meier estimate of survival to 12 months of age was 67%, and to 4 years was 56%. In CL08, the Kaplan-Meier estimate of survival to 12 months of age was 90%, and to 3 years was 80%. In the combined population, the Kaplan-Meier estimate of survival to 12 months of age was 79%, and to 5 years was 68%. In Fig. 2, the survival analysis for the combined population is compared with a similar analysis of 12-month data from untreated infants with growth failure due to rapidly progressive LAL-D (natural history study LAL-1-NH01), in which none of the untreated infants survived past 12 months of age [9].
Growth and functional development
Median weight-for-age z scores in VITAL and CL08 are shown in Fig. 3; the horizontal line at − 2 standard deviations indicates the threshold for underweight established by the United Nations Children’s Fund [14]. The median (range) z score increased from − 1.875 (− 4.79 to 0.74; n = 8) at baseline to − 0.669 (− 1.41 to 1.87; n = 5) at week 240 (month 60; last visit with data available for > 4 patients) in VITAL, and from − 2.515 (− 4.45 to 0.84; n = 10) at baseline to 0.711 (− 0.51 to 1.08; n = 5) at week 156 in CL08. The median (range) length-for-age z score increased from − 2.290 (− 3.91 to 0.87; n = 8) at baseline to − 0.386 (− 1.90 to 1.76; n = 5) at week 240 (month 60; last visit with data available for > 2 patients) in VITAL, and from − 1.900 (− 3.20 to 0.47; n = 9) at baseline to 0.209 (− 1.20 to 0.73; n = 5) at week 156 in CL08. Median mid-upper arm circumference-for-age z scores in VITAL and CL08 are shown in Fig. 4. The median (range) mid-upper arm circumference-for-age z score increased from − 4.450 (− 5.98 to − 2.50; n = 4) at baseline to − 0.490 (− 1.96 to 0.43; n = 3) at week 84 (month 21; last visit with data available for > 2 patients) in VITAL, and from − 4.200 (− 5.88 to − 1.73; n = 5) at baseline to 0.190 (− 1.42 to 1.08; n = 5) at week 84 (last visit with data available for > 2 patients) in CL08.
In both studies, patients remained generally stable in all 4 skill areas of the Denver II Developmental Screening Test (language, fine motor–adaptive, gross motor, personal-social) through end of study. In VITAL, none of the surviving patients was untestable on a postdose assessment, and no patient treated for at least 24 weeks tested as “abnormal” in any skill area at any time point. In CL08, no patient treated for at least 24 weeks was untestable in any skill area at any subsequent time point.
Liver, hematologic, and lipid effects
Liver function, hematologic measures, and lipid levels at baseline and end of study are shown in Table 2. Median alanine aminotransferase (ALT) levels over time in VITAL and CL08 are illustrated in Fig. 5. In VITAL, among the 6 patients who survived beyond week 4, 4 had abnormal ALT levels at baseline, and all 4 experienced normalization of ALT during sebelipase alfa treatment. Similarly, 4 of 6 patients who survived beyond week 4 had abnormal aspartate aminotransferase (AST) levels at baseline, and all 4 experienced normalization of AST during treatment. In CL08, normalization of ALT was achieved for the 3 patients with abnormal baseline ALT levels, and normalization of AST was achieved for 50% of patients with abnormal baseline AST levels. As shown in Table 2, decreases in median liver and spleen volume over time were noted in both studies.
Table 2
Liver, Hematologic, and Lipid Effects
|
VITAL (N = 9)
|
CL08 (N = 10)
|
Parameter
|
Baseline (n = 9),
Median (Range)
|
End of Studya (n = 4),
Median (Range)
|
Baseline (n = 9),
Median (Range)
|
End of Studyb (n = 5),
Median (Range)
|
ALT
|
|
|
|
|
U/L
|
145.0 (16–297)
|
26.5 (18–38)
|
37.0 (28–248)
|
29.0 (22–106)
|
µkat/L
|
2.42 (0.3–5.0)
|
0.44 (0.3–0.6)
|
0.62 (0.5–4.1)
|
0.48 (0.4–1.8)
|
AST
|
|
|
|
|
U/L
|
125.0 (71–716)
|
44.5 (41–54)
|
99.5 (56–441)c
|
44.0 (38–110)
|
µkat/L
|
2.09 (1.2–12.0)
|
0.74 (0.7–0.9)
|
1.66 (0.9–7.4)c
|
0.73 (0.6–1.8)
|
Ferritin
|
|
|
|
|
µg/L (ng/mL)
|
586.3 (253–48,740)d
|
93.5 (42–123)
|
1750.5 (481–3020)e
|
62.1 (49–75)
|
Albumin, g/L
|
29.0 (13–40)
|
32.0 (27–37)
|
20.0 (18–29)
|
33.0 (20–37)f
|
Hemoglobin, g/L
|
93.0 (1–103)
|
115.5 (99–123)
|
90.0 (81–131)d
|
113.0 (103–129)f
|
Total cholesterol
|
|
|
|
|
mg/dL
|
139.2 (67–225)g
|
112.1 (93–131)h
|
125.7 (97–1063)i
|
106.3 (85–205)f
|
mmol/L
|
3.6 (2–6)g
|
2.9 (2–3)h
|
3.3 (3–28)i
|
2.8 (2–5)f
|
LDL-C
|
|
|
|
|
mg/dL
|
109.4 (19–194)g
|
64.2 (63–75)h
|
119.0 (62–143)h
|
76.6 (53–137)h
|
mmol/L
|
2.8 (0.5–5)g
|
1.7 (2–2)h
|
3.1 (2–4)h
|
2.0 (1–4)h
|
HDL-C
|
|
|
|
|
mg/dL
|
8.9 (0–10)g
|
18.9 (13–19)h
|
9.4 (8–12)f
|
13.1 (13–29)h
|
mmol/L
|
0.2 (0.0–0.3)g
|
0.5 (0.3–0.5)h
|
0.2 (0.2–0.3)f
|
0.3 (0.3–0.8)h
|
Triglycerides
|
|
|
|
|
mg/dL
|
163.9 (31–218)g
|
99.2 (90–237)h
|
265.7 (71–424)g
|
151.1 (133–195)h
|
mmol/L
|
1.9 (0.4–3)g
|
1.1 (1–3)h
|
3.0 (0.8–5)g
|
1.7 (2–2)h
|
Liver volume, MN
|
3.4 (3–4)h
|
1.6 (0.3–3)h,j
|
3.2 (0.1–4)d
|
1.9 (1–2)e
|
Spleen volume, MN
|
7.0 (3–11)e
|
2.6 (2–7)h,j
|
5.8 (0.7–15)c
|
4.0 (2–6)e
|
ALT, alanine aminotransferase; AST, aspartate aminotransferase; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MN, multiples of normal. |
a Week 240 (month 60; last visit with n > 2). |
b Week 156 (month 39). |
c n = 8. |
d n = 7. |
e n = 2. |
f n = 4. |
g n = 5. |
h n = 3. |
i n = 6. |
j Week 120 (month 30; last visit with n > 1). |
Marked decreases in median serum ferritin levels occurred from baseline to end of study in both studies and median albumin levels and median hemoglobin levels increased in both studies (Table 2). Depending on the clinical status, patients received transfusions or blood products as part of their clinical care.
Transfusion-free hemoglobin normalization (TFHN) of at least 4 weeks (short-term TFHN)—which meant that hemoglobin levels were consistently above the age-adjusted lower limit of normal over a minimum period of 4 weeks, with no transfusions during this period or for 2 weeks prior to the first hemoglobin measurement in the period—was achieved by the 6 (100%) patients in VITAL who were eligible for assessment, which included the 3 patients who had low hemoglobin levels at baseline. The estimated median (95% confidence interval [CI]) time to achieve TFHN was 4.6 (0.3–16.6) months. Two of these patients also achieved TFHN maintenance of 13 weeks or more (sustained early TFHN). In CL08, short-term TFHN was achieved by 7 (70%) patients, with an estimated median (95% CI) time to achieve TFHN of 5.5 (3.7–19.6) months. Most patients maintained TFHN for at least 13 weeks; however, no patient met the formal criterion for TFHN maintenance, because TFHN was not attained until after week 8.
Median (range) levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides are summarized in Table 2; in general, lipid data were more limited, but available data suggest trends toward improvement in the serum lipid profile of patients in both studies. In VITAL, 4 patients received lipid-modifying agents (cholestyramine, n = 3; other, n = 1). In CL08, lipid-modifying medication (fenofibrate 145 mg once daily) was routinely administered to 1 patient throughout the study. This patient also received 2 potentially lipid-modifying agents (Carthamus tinctorius oil and omega-3-acid ethyl ester) from day 651 through end of study; 2 other patients received treatment with transient courses of lipid-modifying agents (atorvastatin or cholestyramine).
Nutritional status
Treatment with sebelipase alfa was associated with a trend toward normalization of diet, although most patients still required some form of nutritional modification (eg, medium-chain triglyceride formula, fat-restricted diet, or fat-soluble vitamin supplementation). In the combined studies, 9 of 13 surviving patients required parenteral nutrition at some point during the study, typically at initiation of therapy or during intercurrent illness. In both studies, frequent adjustments were made to meet the nutritional needs of each patient during treatment.
Safety
A total of 1249 infusions were administered in VITAL, and 1193 infusions were administered in CL08. Treatment-emergent adverse events (TEAEs) were reported for all 19 patients in the 2 studies (Table 3). No patient discontinued treatment because of TEAEs. Ninety-five percent of TEAEs in VITAL and 98% in CL08 were mild or moderate in severity; 4 patients (44%) in VITAL and 7 patients (70%) in CL08 experienced 1 or more severe TEAEs. The most frequently reported TEAEs that were considered related or possibly related to treatment (occurring in ≥ 30% of patients) were: vomiting, pyrexia, and urticaria in VITAL, and tachycardia, vomiting, pyrexia, irritability, agitation, respiratory distress, tachypnea, and urticaria in CL08. Serious adverse events (SAEs) were reported in all 19 patients. Serious adverse events related or possibly related to study drug were reported in 6 patients, 1 (11%) in VITAL and 5 (50%) in CL08; with the exception of 1 patient in CL08, these were infusion-associated reactions (IARs). The patient in CL08 who had a non-IAR SAE had initiated sebelipase alfa treatment at 2 weeks of age and developed hypertension and moderate proteinuria at 6 months of age, along with high anti-drug antibody (ADA) titers. The patient received treatment with amlodipine, rituximab, and bortezomib, and underwent HSCT at 30 months. Six months after HSCT, the patient developed nephrotic syndrome, suspected to have resulted from the deposition of circulating soluble immune complexes in the glomerulus, and received multiple albumin infusions, furosemide, prednisolone, lisinopril, and bortezomib. The patient’s proteinuria had almost normalized by 8 months [15].
Table 3
Summary of Adverse Events (Full Analysis Set)
Event
|
VITAL (N = 9),
n (%)
|
CL08 (N = 10),
n (%)
|
Any TEAE
|
9 (100)
|
10 (100)
|
Mild or moderate TEAEs
|
0 (0)
|
3 (30)
|
Any treatment-related or possibly related TEAE
|
6 (67)
|
8 (80)
|
Any SAE
|
9 (100)
|
10 (100)
|
Any treatment-related or possibly related SAE
|
1 (11)
|
5 (50)
|
Any IAR
|
5 (56)
|
8 (80)
|
Mild or moderate IARs
|
5 (56)
|
6 (60)
|
Dose modification due to a TEAEa
|
7 (78)
|
7 (70)
|
Discontinuation due to a TEAE
|
0 (0)
|
0 (0)
|
Death
|
4 (44)
|
2 (20)
|
IAR, infusion-associated reaction; SAE, serious adverse event; TEAE, treatment-emergent adverse event. |
a Includes dose increases, dose decreases, drug interruptions, and study drug withdrawal. |
Infusion-associated reactions were reported in 13 of 19 patients. Of the 54 IARs reported in VITAL, 94% were mild or moderate in severity, and of the 98 IARs reported in CL08, 88% were mild or moderate in severity. The most frequently reported IARs in VITAL were pyrexia (33%), urticaria (33%), vomiting (33%), tachycardia (22%), and pallor (22%); in CL08, they were tachycardia (70%), pyrexia (60%), irritability (50%), agitation (40%), and urticaria (40%). One patient in CL08 experienced IARs that required a per-protocol desensitization procedure involving administration of lower concentration solutions of sebelipase alfa over prolonged infusion times, with stepwise increases in infusion rate and an increase in dose from 0.35 mg/kg once weekly (qw) to the full planned dose of 3.0 mg/kg qw over the initial 4 infusions of the desensitization period [16]. In all other patients IARs were successfully managed and resolved using local regular treatment protocols, as in studies of other enzyme replacement therapies [17].
As noted previously, 6 patients died during the studies; none of the deaths was considered to be related to sebelipase alfa treatment. In VITAL, 3 of the 4 patients died after receiving up to 4 doses of sebelipase alfa (1 patient died at 2.8 months of age due to liver failure as a result of LAL-D; 1 patient died at 3.0 months of age due to peritoneal hemorrhage following a non–study-related procedure [abdominal paracentesis]; and 1 patient died at 4.3 months of age due to cardiac arrest). One patient in VITAL had sudden cardiac death at 15.0 months of age. In CL08, 1 patient died at 4.9 months of age from pericardial effusion due to necrosis of the atrial wall associated with leakage from an indwelling intravenous (IV) line, and 1 patient died at 13.8 months of age from septicemia.
Table 4 summarizes the final doses of sebelipase alfa among surviving patients at the end of the VITAL and CL08 studies and immunogenicity results during the studies. One patient in VITAL switched to an every-other-week (qow) dosing regimen beginning at week 122, but ultimately reverted back to a qw dosing regimen beginning at week 155 due to elevated serum transaminase levels during qow dosing; serum transaminases returned to within the normal range with qw dosing. Three additional patients in VITAL had isolated instances of qow dosing during the study, including 1 patient who was intermittently hospitalized due to intercurrent adenovirus and rotavirus infections. No patient in CL08 switched to a qow regimen.
Table 4
Sebelipase Alfa Dosing Status and Immunogenicity
|
VITAL (N = 9)
|
CL08 (N = 10)
|
Final dose, surviving patients, n/N
|
5/9
|
8/10
|
1.0 mg/kg qw, n
|
0
|
1a
|
3.0 mg/kg qw, n
|
3
|
3
|
5.0 mg/kg qw, n
|
2
|
4
|
Week of first 3.0 mg/kg dose, median (range)b
|
14 (6–91)
|
12 (4–58)
|
Immunogenicity during the studyc
|
|
|
Anti-drug antibody test, n positive/N tested
|
4/7
|
6/10
|
Neutralizing assay, n positive/N tested
|
3/4
|
6/6
|
Inhibit cellular uptake of LAL
|
3/4
|
6/6
|
Inhibit LAL enzyme activity
|
2/4d
|
6/6
|
LAL, lysosomal acid lipase; qw, once weekly. |
a One patient received successive dose escalations up to a maximum dose of 7.5 mg/kg qw. This patient had subsequent successive dose reductions to 1.0 mg/kg qw after a successfully engrafted bone marrow transplant at week 101. |
b Among surviving patients. |
c Among all patients with posttreatment assessments. |
d These patients also had neutralizing antibodies that inhibit cellular uptake of LAL. |
In VITAL, among 7 patients with posttreatment immunogenicity data, 4 (57%) were positive for ADAs during at least 1 assessment. Anti-drug antibody positivity was first detected at week 5 for 1 patient, week 8 for 2 patients, and week 59 for 1 patient, and ADA positivity persisted in all 4 patients. Three of the 4 ADA-positive patients tested positive for neutralizing antibodies that inhibit the cellular uptake of LAL, 2 of whom also tested positive for antibodies that inhibit LAL enzyme activity. In CL08, 6 patients developed ADAs during treatment, with positivity first detected at week 5 for 1 patient, week 8 for 2 patients, and weeks 12, 20, and 60 (1 patient each). The ADA positivity persisted in 3 patients. All 6 ADA-positive patients tested positive for neutralizing antibodies that inhibited both LAL enzyme activity and cellular uptake. Data suggested that neutralizing antibodies had an impact on clinical response in 3 patients. These 3 patients had notably higher ADA titers than the other 3 ADA-positive patients, and the disease-causing mutation for all 3 unrelated patients was a deletion of the entire LIPA gene, including the neighboring 24 cholesterol-hydroxylase gene. In all 3 patients, the development of high ADA titers was associated with decreased weight for age and other parameters of failure to thrive, suggestive of decreased clinical efficacy. Loss of efficacy resulted in sebelipase alfa dose increases (all 3 patients) and other clinical measures, such as bone marrow transplant and immunomodulatory therapy with bortezomib (n = 1) and immunomodulatory therapy and immune supplementation therapy with IV immunoglobulin, rituximab, and bortezomib, followed by HSCT and bortezomib (n = 1). There was no clear relationship between ADA status and the risk of IARs.