Cholesterol Ester Storage Disease(CESD), LAL-Deficiency, Lysosomal Acid Lipase Deficiency
Conditions
Keywords
Enzyme Replacement Therapy (ERT), Lysosomal Storage Disease, Late Onset Lysosomal Acid Lipase (LAL) Deficiency, Acid cholesteryl ester hydrolase deficiency, type 2, Acid lipase disease, Cholesterol ester hydrolase deficiency, LAL Deficiency, LIPA Deficiency, Wolman disease
Brief summary
This was the first clinical study of SBC-102 (sebelipase alfa) for the treatment of Lysosomal Acid Lipase (LAL) Deficiency. It was an open-label dose escalation study in adult participants with liver dysfunction due to LAL Deficiency and was designed to examine 3 doses of sebelipase alfa. The targeted number for this study was 9 evaluable participants.
Detailed description
The study was composed of a screening period, a treatment period, and a post-treatment follow-up period (including an End of Study visit). Participants who successfully completed screening assessments to determine study eligibility were allocated to 3 sequential cohorts (0.35, 1, or 3 milligrams/kilogram \[mg/kg\]). Within each cohort, one participant was initially dosed and, if sebelipase alfa was deemed safe and well tolerated in this participant (based on at least 24 hours of monitoring), dosing was allowed to be initiated for the remaining participants in the cohort. Initiation of dosing in the next cohort occurred only after all participants in the preceding cohort had been monitored for at least 5 days after the second infusion, without any evidence of significant safety signals, and an independent Safety Committee had reviewed the cumulative safety data and provided their recommendation on the acceptability of beginning dosing in the next cohort. Cholesteryl Ester Storage Disease (CESD) is the late onset phenotype for LAL Deficiency, a lysosomal storage disorder, which also has an early onset phenotype known as Wolman disease that primarily affects infants. CESD can present in childhood but often goes unrecognized until adulthood when the underlying pathology is advanced. Many of the signs and symptoms are common to participants with other liver conditions. CESD is an autosomal recessive genetic condition and is characterized by hepatomegaly, persistently abnormal liver function tests and type II hyperlipidemia. Splenomegaly and evidence of mild hypersplenism may affect some participants. Untreated, CESD may lead to fibrosis, cirrhosis, liver failure and death.
Interventions
DRUGSebelipase alfa 0.35 mg/kg
Sebelipase alfa is a recombinant human lysosomal acid lipase.
DRUGSebelipase alfa 1 mg/kg
Sebelipase alfa is a recombinant human lysosomal acid lipase.
DRUGSebelipase alfa 3 mg/kg
Sebelipase alfa is a recombinant human lysosomal acid lipase.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female participants ≥ 18 and ≤ 65 years of age * Documented decreased LAL activity * Evidence of liver involvement
Exclusion criteria
* Clinically significant concurrent disease, serious inter-current illness, concomitant medications or other extenuating circumstances * Clinically significant abnormal values on laboratory screening tests, other than liver function or lipid panel tests * Aspartate aminotransferase and/or alanine aminotransferase persistently elevated \> 3x upper limit of normal at screening * Previous hemopoietic bone marrow or liver transplant * Current history of alcohol abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | Screening up to Day 52 | Safety and tolerability of sebelipase alfa was primarily assessed by monitoring the number of participants reporting treatment-emergent adverse events (TEAEs), including serious adverse events, and infusion-related reactions (IRRs). The number of participants who discontinued from the study due to a TEAE is also presented. An IRR was defined as any adverse event that occurred between the start of the infusion and 4 hours after completion of the infusion and was assessed by the Investigator as at least possibly related to study drug. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. |
Countries
Czechia, France, United Kingdom, United States
Participant flow
Pre-assignment details
Participants were screened for eligibility for enrollment in this study (LAL-CL01). Nine participants met all enrollment criteria and were enrolled and allocated to 1 of 3 cohorts.
Participants by arm
| Arm | Count |
|---|---|
| Sebelipase Alfa 0.35 mg/kg Cohort 1: Participants were administered qw infusions of 0.35 mg/kg sebelipase alfa. | 3 |
| Sebelipase Alfa 1 mg/kg Cohort 2: Participants were administered qw infusions of 1 mg/kg sebelipase alfa. | 3 |
| Sebelipase Alfa 3 mg/kg Cohort 3: Participants were administered qw infusions of 3 mg/kg sebelipase alfa. | 3 |
| Total | 9 |
Baseline characteristics
| Characteristic | Sebelipase Alfa 0.35 mg/kg | Sebelipase Alfa 1 mg/kg | Sebelipase Alfa 3 mg/kg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 3 Participants | 9 Participants |
| Age, Continuous | 32.3 years STANDARD_DEVIATION 7.57 | 35.3 years STANDARD_DEVIATION 14.22 | 27.0 years STANDARD_DEVIATION 12.17 | 31.6 years STANDARD_DEVIATION 10.74 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs)
Safety and tolerability of sebelipase alfa was primarily assessed by monitoring the number of participants reporting treatment-emergent adverse events (TEAEs), including serious adverse events, and infusion-related reactions (IRRs). The number of participants who discontinued from the study due to a TEAE is also presented. An IRR was defined as any adverse event that occurred between the start of the infusion and 4 hours after completion of the infusion and was assessed by the Investigator as at least possibly related to study drug. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Time frame: Screening up to Day 52
Population: Safety Analysis Set: All participants who received any full or partial dose of sebelipase alfa in this study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sebelipase Alfa 0.35 mg/kg | Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | TEAEs | 1 participants |
| Sebelipase Alfa 0.35 mg/kg | Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | SAEs | 0 participants |
| Sebelipase Alfa 0.35 mg/kg | Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | IRRs | 0 participants |
| Sebelipase Alfa 0.35 mg/kg | Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | TEAEs Leading to Study Discontinuation | 0 participants |
| Sebelipase Alfa 1 mg/kg | Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | TEAEs Leading to Study Discontinuation | 0 participants |
| Sebelipase Alfa 1 mg/kg | Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | TEAEs | 3 participants |
| Sebelipase Alfa 1 mg/kg | Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | IRRs | 0 participants |
| Sebelipase Alfa 1 mg/kg | Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | SAEs | 0 participants |
| Sebelipase Alfa 3 mg/kg | Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | TEAEs Leading to Study Discontinuation | 0 participants |
| Sebelipase Alfa 3 mg/kg | Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | SAEs | 0 participants |
| Sebelipase Alfa 3 mg/kg | Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | IRRs | 0 participants |
| Sebelipase Alfa 3 mg/kg | Number Of Participants Reporting TEAEs And Infusion-Related Reactions (IRRs) | TEAEs | 3 participants |