Safety, Tolerability and Pharmacokinetics of SBC-102 (Sebelipase Alfa) in Adult Participants With Lysosomal Acid Lipase Deficiency

Phase 1

Completed

• Conditions: LAL-Deficiency; Lysosomal Acid Lipase Deficiency; Cholesterol Ester Storage Disease(CESD)
• Interventions: Drug: Sebelipase alfa 0.35 mg/kg; Drug: Sebelipase alfa 3 mg/kg; Drug: Sebelipase alfa 1 mg/kg

• Registration Number: NCT01307098
• Lead Sponsor: Alexion Pharmaceuticals, Inc.

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.

Study Timeline

• Study First Submitted: 2011-03-01
• Study First Submitted QC: 2011-03-01
• Study First Posted: 2011-03-02
• Study Start: 2011-04-25
• Primary Completion: 2012-01-06
• Study Completion: 2012-01-06
• Results First Submitted: 2018-10-30
• Status Verified: 2018-12
• Results First Submitted QC: 2018-12-10
• Last Update Submitted: 2018-12-10
• Results First Posted: 2018-12-11
• Last Update Posted: 2018-12-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 9

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sebelipase alfa 0.35 mg/kg	Sebelipase alfa 0.35 mg/kg	Cohort 1: Participants were administered once weekly (qw) infusions of 0.35 mg/kg sebelipase alfa.
Sebelipase alfa 3 mg/kg	Sebelipase alfa 3 mg/kg	Cohort 3: Participants were administered qw infusions of 3 mg/kg sebelipase alfa.
Sebelipase alfa 1 mg/kg	Sebelipase alfa 1 mg/kg	Cohort 2: Participants were administered qw infusions of 1 mg/kg sebelipase alfa.

Primary Outcome Measures

Name	Time	Method
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.